Novel compounds

ABSTRACT

Compounds of formula (I) and salts thereof: 
     
       
         
         
             
             
         
       
     
     wherein R 1  is n-C 4-6 alkyl or C 1-2 alkoxyC 1-2 alkyl-; R 2  is hydrogen or methyl; each R 3  is hydroxy, halo or n-C 1-3 alkyl; m is an integer having a value of 2 to 4; n is an integer having a value of 0 to 3; and p is an integer having a value of 0 to 2, are inducers of human interferon. Compounds which induce human interferon may be useful in the treatment of various disorders, for example the treatment of allergic diseases and other inflammatory conditions, for example allergic rhinitis and asthma, infectious diseases and cancer, and may also be useful as vaccine adjuvants.

This application is a continuation of U.S. application Ser. No.15/370,211 filed on Dec. 6, 2016, which is a continuation of U.S.application Ser. No. 14/443,932 filed on May 19, 2015, which is aNational Stage Entry of PCT/US13/70472, which claims priority from U.S.Provisional Application 61/774,087 filed on Mar. 7, 2013, and U.S.Provisional Application 61/728,390 filed on Nov. 20, 2012, all of whichare incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds, processes for theirpreparation, compositions containing them, to their use in the treatmentof various disorders in particular allergic diseases and otherinflammatory conditions for example allergic rhinitis and asthma,infectious diseases, and cancer, and as vaccine adjuvants.

BACKGROUND OF THE INVENTION

Vertebrates are constantly threatened by the invasion of microorganismsand have evolved mechanisms of immune defence to eliminate infectivepathogens. In mammals, this immune system comprises two branches; innateimmunity and acquired immunity. The first line of host defence is theinnate immune system, which is mediated by macrophages and dendriticcells. Acquired immunity involves the elimination of pathogens at thelate stages of infection and also enables the generation ofimmunological memory. Acquired immunity is highly specific, due to thevast repertoire of lymphocytes with antigen-specific receptors that haveundergone gene rearrangement.

Central to the generation of an effective innate immune response inmammals are mechanisms which bring about the induction of interferonsand other cytokines which act upon cells to induce a number of effects.In man, the type I interferons are a family of related proteins encodedby genes on chromosome 9 and encoding at least 13 isoforms of interferonalpha (IFNα) and one isoform of interferon beta (IFNβ). Interferon wasfirst described as a substance which could protect cells from viralinfection (Isaacs & Lindemann, J. Virus Interference. Proc. R. Soc. Lon.Ser. B. Biol. Sci. 1957: 147, 258-267). Recombinant IFNα was the firstapproved biological therapeutic and has become an important therapy inviral infections and in cancer. As well as direct antiviral activity oncells, interferons are known to be potent modulators of the immuneresponse, acting on cells of the immune system (Gonzalez-Navajas J. M.et al Nature Reviews Immunology, 2012; 2, 125-35).

Toll-like receptors (TLRs) are a family of ten Pattern RecognitionReceptors described in man (Gay, N. J. et al, Annu. Rev. Biochem., 2007:46, 141-165). TLRs are expressed predominantly by innate immune cellswhere their rôle is to monitor the environment for signs of infectionand, on activation, mobilise defence mechanisms aimed at the eliminationof invading pathogens. The early innate immune-responses triggered byTLRs limit the spread of infection, while the pro-inflammatory cytokinesand chemokines that they induce lead to recruitment and activation ofantigen presenting cells, B cells, and T cells. The TLRs can modulatethe nature of the adaptive immune-responses to give appropriateprotection via dendritic cell-activation and cytokine release (Akira S.et al, Nat. Immunol., 2001: 2, 675-680). The profile of the responseseen from different TLR agonists depends on the cell type activated.

TLR7 is a member of the subgroup of TLRs (TLRs 3, 7, 8, and 9),localised in the endosomal compartment of cells which have becomespecialised to detect non-self nucleic acids. TLR7 plays a key rôle inanti-viral defence via the recognition of ssRNA (Diebold S. S. et al,Science, 2004: 303, 1529-1531; and Lund J. M. et al, PNAS, 2004: 101,5598-5603). TLR7 has a restricted expression-profile in man and isexpressed predominantly by B cells and plasmacytoid dendritic cells(pDC), and to a lesser extent by monocytes. Plasmacytoid DCs are aunique population of lymphoid-derived dendritic cells (0.2-0.8% ofPeripheral Blood Mononuclear Cells (PBMCs)) which are the primary type Iinterferon-producing cells secreting high levels of interferon-alpha(IFNα) and interferon-beta (IFNβ) in response to viral infections (LiuY-J, Annu. Rev. Immunol., 2005: 23, 275-306).

Administration of a small molecule compound which could stimulate theinnate immune response, including the activation of type I interferonsand other cytokines via Toll-like receptors, could become an importantstrategy for the treatment or prevention of human diseases. Smallmolecule agonists of TLR7 have been described which can induceinterferon alpha in animals and in man (Takeda K. et al, Annu. Rev.Immunol., 2003: 21, 335-76). TLR7 agonists include imidazoquinolinecompounds such as imiquimod and resiquimod, oxoadenine analogues andalso nucleoside analogues such as loxoribine and 7-thia-8-oxoguanosinewhich have long been known to induce interferon alpha (Czarniecki. M.,J. Med, Chem., 2008: 51, 6621-6626; Hedayat M. et al, Medicinal ResearchReviews, 2012: 32, 294-325). This type of immunomodulatory strategy hasthe potential to identify compounds which may be useful in the treatmentof allergic diseases (Moisan J. et al, Am. J. Physiol. Lung Cell Mol.Physiol., 2006: 290, L987-995), viral infections (Horcroft N. J. et al,J. Antimicrob. Chemther, 2012: 67, 789-801), cancer (Krieg A., Curr.Oncol. Rep., 2004: 6(2), 88-95), other inflammatory conditions such asirritable bowel disease (Rakoff-Nahoum S., Cell., 2004, 23, 118(2):229-41), and as vaccine adjuvants (Persing et al. Trends Microbiol.2002: 10(10 Suppl), S32-7).

More specifically, allergic diseases are associated with a Th2-biasedimmune-response to allergens. Th2 responses are associated with raisedlevels of IgE, which, via its effects on mast cells, promotes ahypersensitivity to allergens, resulting in the symptoms seen, forexample, in asthma and allergic rhinitis. In healthy individuals theimmune-response to allergens is more balanced with a mixed Th2/Th1 andregulatory T cell response. TLR7 ligands have been shown to reduce Th2cytokine and enhance Th1 cytokine release in vitro and to ameliorateTh2-type inflammatory responses in allergic lung models in vivo (DuechsM. J., Pulmonary Pharmacology & Therapeutics, 2011: 24, 203-214; Fili L.et al, J. All. Clin. Immunol., 2006: 118, 511-517; Tao et al, Chin. Med.J., 2006: 119, 640-648; Van L. P. Eur. J. Immunol., 2011: 41,1992-1999). Thus TLR7 ligands have the potential to rebalance theimmune-response seen in allergic individuals and lead to diseasemodification. Recent clinical studies with the TLR7 agonist have shownrepeated intranasal stimulation of TLR7 to produce a sustained reductionin the responsiveness to allergen in patients with both allergicrhinitis and allergic asthma (Greiff L. Respiratory Research, 2012: 13,53; Leaker B. R. et al, Am. J. Respir. Crit. Care Med., 2012: 185,A4184).

In the search for novel small molecule inducers of human interferon IFNαan assay strategy has been developed to characterise small molecule(regardless of mechanism) which is based on stimulation of primary humandonor cells or whole blood with compounds, and is disclosed herein.

SUMMARY OF THE INVENTION

In a first aspect, the present invention is directed to compounds offormula (I) and salts thereof:

wherein:R₁ is n-C₄₋₆alkyl or C₁₋₂alkoxyC₁₋₂alkyl-;R₂ is hydrogen or methyl;each R₃ is hydroxy, halo or n-C₁₋₃alkyl;m is an integer having a value of 2 to 4;n is an integer having a value of 0 to 3;p is an integer having a value of 0 to 2.

Certain compounds of the invention have been shown to be inducers ofhuman interferon and may possess a desirable developability profilecompared to known inducers of human interferon. In addition, certaincompounds of the invention may show selectivity for IFNα with respect toTNFα. Compounds which induce human interferon may be useful in thetreatment of various disorders, for example the treatment of allergicdiseases and other inflammatory conditions, for example allergicrhinitis and asthma, the treatment of infectious diseases and cancer.Accordingly, the invention is further directed to pharmaceuticalcompositions comprising a compound of formula (I), or a pharmaceuticallyacceptable salt thereof. The present invention is further directed tomethods of treatments of disorders associated therewith using a compoundof formula (I) or a pharmaceutically acceptable salt thereof, or apharmaceutical composition comprising a compound of formula (I) or apharmaceutically acceptable salt thereof.

The compounds of the invention may also have use as vaccine adjuvants.Consequently, the present invention is further directed to a vaccinecomposition comprising a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, and an antigen or antigen composition.

Certain compounds of the invention are potent immunomodulators andaccordingly, care should be exercised in their handling.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the present invention is directed to compounds offormula (I) and salts thereof:

wherein:R₁ is n-C₄₋₆alkyl or C₁₋₂alkoxyC₁₋₂alkyl-;R₂ is hydrogen or methyl;each R₃ is hydroxy, halo or n-C₁₋₃alkyl;m is an integer having a value of 2 to 4;n is an integer having a value of 0 to 3;p is an integer having a value of 0 to 2.

In a further aspect, R₁ is n-butyl.

In a further aspect, R₁ is ethoxymethyl.

In a further aspect, R₁ is 2-methoxyethyl.

In a further aspect, R₂ is hydrogen.

In a further aspect, R₂ is methyl.

In a further aspect, m is an integer having a value of 2, 3 or 4.

In a further aspect, n is an integer having a value of 1 or 2.

In a further aspect, p is 0.

In a further aspect, R₃ is hydroxy or halo.

In a further aspect, p is 1 and R₃ is hydroxy or fluoro.

In a further aspect, p is 2 and R₃ is fluoro.

Examples of compounds of formula (I) are provided in the followinggroup, and form a further aspect of the invention:

-   2-Butyl-7-(6-(piperidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   2-Butyl-7-(5-(piperidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   2-Butyl-7-(4-(piperidin-1-yl)butyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   2-(Ethoxymethyl)-7-(6-(piperidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   2-(2-Methoxyethyl)-7-(6-(piperidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   2-Butyl-6-methyl-7-(6-(piperidin-1-yl)    hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   2-Butyl-6-methyl-7-(5-(piperidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   2-Butyl-6-methyl-7-(4-(piperidin-1-yl)butyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   2-Butyl-7-(5-(pyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   2-Butyl-7-(6-(pyrrolidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   2-Pentyl-7-(6-(piperidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   7-(5-(Azepan-1-yl)pentyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   7-(4-(Azepan-1-yl)butyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   2-Butyl-6-methyl-7-(6-(pyrrolidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   7-(6-(Azetidin-1-yl)    hexyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   2-Butyl-6-methyl-7-(5-(pyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   7-(5-(Azetidin-1-yl)    pentyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   7-(5-(Azetidin-1-yl)    pentyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   2-Butyl-6-methyl-7-(4-(pyrrolidin-1-yl)butyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   2-Butyl-7-(5-(4,4-difluoropiperidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   2-Butyl-7-(5-(4-fluoropiperidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   7-(5-(4-Fluoropiperidin-1-yl)    pentyl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   1-(5-(4-Amino-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pentyl)    piperidin-4-ol;-   (R)-2-Butyl-7-(5-(3-fluoropyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   (S)-2-Butyl-7-(5-(3-fluoropyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   (R)-7-(5-(3-Fluoropyrrolidin-1-yl)pentyl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   (S)-7-(5-(3-Fluoropyrrolidin-1-yl)pentyl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   (S)-1-(5-(4-Amino-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pentyl)    pyrrolidin-3-ol; and-   1-(5-(4-Amino-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)    pentyl)azetidin-3-ol;-   7-(6-(Azepan-1-yl)hexyl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   2-Butyl-7-(6-(4-fluoropiperidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   (R)-2-Butyl-7-(6-(3-fluoropyrrolidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   (S)-2-Butyl-7-(6-(3-fluoropyrrolidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   (S)-2-Butyl-7-(5-(2-methylpyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   (R)-2-Butyl-7-(5-(2-methylpyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   2-Butyl-7-(5-(3-methylazetidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   2-Butyl-7-(5-(3-fluoroazetidin-1-yl)    pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   2-Butyl-6-methyl-7-(6-(pyrrolidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   2-Butyl-7-(5-(4-fluoropiperidin-1-yl)pentyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   (S)-2-Butyl-7-(5-(3-fluoropyrrolidin-1-yl)pentyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   (R)-2-Butyl-7-(5-(3-fluoropyrrolidin-1-yl)    pentyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   2-Butyl-7-(5-(3-fluoroazetidin-1-yl)pentyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   2-(2-Methoxyethyl)-7-(5-(pyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine,    and salts thereof.

As used herein, the term “alkyl” refers to a saturated, straighthydrocarbon chain having the specified number of member atoms. Forexample, n-C₄₋₆ alkyl refers to a saturated, straight hydrocarbon chainhaving from 4 to 6 carbon atoms. Unless otherwise stated, alkyl groupsare unsubstituted. The term “alkyl” includes, but is not limited to,n-butyl.

As used herein, the term “alkoxy” refers to a saturated, straighthydrocarbon chain having the specified number of member atoms linked bea single bond to an oxygen atom. For example, C₁₋₂alkoxy refers to analkoxy group having 1 or 2 carbon atoms, which would be referred to asmethoxy or ethoxy respectively.

As used herein, the term “halo” refers to fluoro, chloro, bromo andiodo.

It is to be understood that references herein to compounds of theinvention mean a compound of formula (I) as the free base, or as a salt,for example a pharmaceutically acceptable salt.

In one aspect of the invention, a compound of formula (I) is in the formof a free base.

Salts of the compounds of formula (I) include pharmaceuticallyacceptable salts and salts which may not be pharmaceutically acceptablebut may be useful in the preparation of compounds of formula (I) andpharmaceutically acceptable salts thereof. In one aspect of theinvention, a compound of formula (I) is in the form of apharmaceutically acceptable salt. Salts may be derived from certaininorganic or organic acids.

Examples of salts are pharmaceutically acceptable salts.Pharmaceutically acceptable salts include acid addition salts. For areview on suitable salts see Berge et al., J. Pharm. Sci., 66:1-19(1977).

Examples of pharmaceutically acceptable acid addition salts of acompound of formula (I) include inorganic acids such as, for example,hydrochloric acid, hydrobromic acid, orthophosphoric acid, nitric acid,phosphoric acid, or sulphuric acid, or with organic acids such as, forexample, methanesulphonic acid, ethanesulphonic acid, p-toluenesulphonicacid, acetic acid, propionic acid, lactic acid, citric acid, fumaricacid, malic acid, succinic acid, salicylic acid, maleic acid,glycerophosphoric acid, tartaric, benzoic, glutamic, aspartic,benzenesulphonic, naphthalenesulphonic such as 2-naphthalenesuphonic,hexanoic acid or acetylsalicylic acid.

The invention includes within its scope all possible stoichiometric andnon-stoichiometric forms of the salts of the compounds of formula (I).For example, a dimaleate or hemi-succinate salt of the compound offormula (I).

Salts may be formed using techniques well-known in the art, for exampleby precipitation from solution followed by filtration, or by evaporationof the solvent.

Typically, a pharmaceutically acceptable acid addition salt can beformed by reaction of a compound of formula (I) with a suitable acid(such as hydrobromic, hydrochloric, sulphuric, maleic,p-toluenesulphonic, methanesulphonic, naphthalenesulphonic or succinicacids), optionally in a suitable solvent such as an organic solvent, togive the salt which is usually isolated for example by crystallisationand filtration.

It will be appreciated that many organic compounds can form complexeswith solvents in which they are reacted or from which they areprecipitated or crystallised. These complexes are known as “solvates”.For example, a complex with water is known as a “hydrate”. Solvents withhigh boiling points and/or solvents with a high propensity to formhydrogen bonds such as water, ethanol, iso-propyl alcohol, and N-methylpyrrolidinone may be used to form solvates. Methods for theidentification of solvated include, but are not limited to, NMR andmicroanalysis. Solvates of the compounds of formula (I) are within thescope of the invention. As used herein, the term solvate encompassessolvates of both a free base compound as well as any salt thereof.

Certain of the compounds of the invention may contain chiral atomsand/or multiple bonds, and hence may exist in one or more stereoisomericforms. The present invention encompasses all of the stereoisomers of thecompounds of the invention, including optical isomers, whether asindividual stereoisomers or as mixtures thereof including racemicmodifications. Any stereoisomer may contain less than 10% by weight, forexample less than 5% by weight, or less than 0.5% by weight, of anyother stereoisomer. For example, any optical isomer may contain lessthan 10% by weight, for example less than 5% by weight, or less than0.5% by weight, of its antipode.

Certain of the compounds of the invention may exist in tautomeric forms.It will be understood that the present invention encompasses all of thetautomers of the compounds of the invention whether as individualtautomers or as mixtures thereof.

The compounds of the invention may be in crystalline or amorphous form.Furthermore, some of the crystalline forms of the compounds of theinvention may exist as polymorphs, all of which are included within thescope of the present invention. The most thermodynamically stablepolymorphic form or forms of the compounds of the invention are ofparticular interest.

Polymorphic forms of compounds of the invention may be characterised anddifferentiated using a number of conventional analytical techniques,including, but not limited to, X-ray powder diffraction (XRPD), infraredspectroscopy (IR), Raman spectroscopy, differential scanning calorimetry(DSC), thermogravimetric analysis (TGA) and solid-state nuclear magneticresonance (ssNMR).

The present invention also includes all suitable isotopic variations ofa compound of formula (I) or a pharmaceutically acceptable salt thereof.An isotopic variation of a compound of formula (I), or apharmaceutically acceptable salt thereof, is defined as one in which atleast one atom is replaced by an atom having the same atomic number butan atomic mass different from the atomic mass usually found in nature.Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,fluorine and chlorine such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ¹⁸F and³⁶Cl, respectively. Certain isotopic variations of a compound of formula(1) or a salt or solvate thereof, for example, those in which aradioactive isotope such as ³H or ¹⁴C is incorporated, are useful indrug and/or substrate tissue distribution studies. Tritiated, i.e., ³H,and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for theirease of preparation and detectability. Further, substitution withisotopes such as deuterium, i.e., ²H, may afford certain therapeuticadvantages resulting from greater metabolic stability, for example,increased in vivo half-life or reduced dosage requirements and hence maybe preferred in some circumstances. Isotopic variations of a compound offormula (I), or a pharmaceutically salt thereof, can generally beprepared by conventional procedures such as by the illustrative methodsor by the preparations described in the Examples hereafter usingappropriate isotopic variations of suitable reagents.

It will be appreciated from the foregoing that included within the scopeof the invention are solvates, hydrates, isomers and polymorphic formsof the compounds of formula (I) and salts and solvates thereof.

Compound Preparation

Accordingly, there is provided a process for the preparation of acompound of formula (I), which process comprises the deprotection of acompound of formula (II):

wherein R₁, R₂, R₃, m, n and p are as defined hereinbefore for acompound of formula (I) and PG is a protecting group, such asbenzyloxymethyl (BOM), 2-(trimethylsilyl)ethoxymethyl (SEM) orp-toluenesufonyl and thereafter, if required, preparing a salt of thecompound so-formed.

For example, a compound of formula (II) wherein PG is equivalent to BOMis dissolved in a suitable solvent, for example methanol or ethanol, andpassed over a suitable catalyst, for example 10% palladium on carbon inthe presence of hydrogen, at a suitable temperature, for example 20-60°C. in an apparatus such as the Thales H-cube™. The product (I) isisolated by removal of the solvent and purification if required.

For example, a compound of formula (II) wherein PG is SEM is dissolvedin a suitable solvent, for example tetrahydrofuran, and reacted withtetrabutylammonium fluoride and ethylenediamine at a suitabletemperature, for example 70° C. The product (I) is isolated by removalof the solvent and purification if required.

A compound of formula (II) may be prepared by reaction of a compound offormula (III):

wherein R₁, R₂, R₃, m, n and p are as hereinbefore defined for acompound of formula (I) with hydrogen in the presence of a catalyst.

For example a compound of formula (III) is dissolved in a suitablesolvent for example methyl alcohol or ethyl alcohol, and passed over asuitable catalyst, for example 10% palladium on carbon, in the presenceof hydrogen at a suitable temperature, for example 20-60° C., in asuitable flow hydrogenation apparatus such as the Thales H-Cube™. Theproduct (II) is isolated by removal of the solvent and purification ifrequired.

When the protecting group is the benzyloxymethyl (BOM) group thereaction to reduction the alkyne can result in the simultaneous removalof the protecting group to afford compounds of formula (I) directly.

A compound of formula (III) may be prepared by reaction of a compound offormula (IV):

wherein R₁ and R₂ are as hereinbefore defined for a compound of formula(I) and Y is a leaving group for example a halogen such as iodine orbromine or an alkyl sulfonate such as a trifluoromethane sulfonate witha compound of formula (V):

wherein R₃, m, n and p are defined for a compound of formula (I).

For example a compound of formula (IV), a compound of formula (V) aredissolved in a suitable solvent, for example N,N-dimethylformamide, inthe presence of copper(I) iodide, a suitable catalyst, for examplebis(triphenylphosphine)palladium(II) dichloride and a suitable base, forexample triethylamine, and heated at a suitable temperature, for example20-55° C. for a suitable period of time, for example 0.5-17 hours. Theproduct (III) is isolated after an aqueous work-up and purification.

A compound of formula (V) may be prepared by reaction of a compound offormula (VI):

wherein m is defined for a compound of formula (I) and X is a leavinggroup such as a halogen, for example chlorine, bromine or iodine, or analkyl sulfonate, for example p-toluenesulfonate, with a compound offormula (VII):

wherein R₃, n and p are as defined for a compound of formula (I).

For example a compound of formula (VI), a compound of formula (VII) anda suitable base, for example sodium hydrogen carbonate, are dissolved ina suitable solvent, for example N,N-dimethylformamide, and heated at asuitable temperature, for example 80-100° C. for a suitable period oftime, for example 16-18 hours. The product (V) is isolated after aqueouswork-up and purification, for example by isolation of a suitablecrystalline salt, for example the oxalate salt.

Compounds of formula (VI) and formula (VII) are either commerciallyavailable or may be prepared by methods described in the literature.

Alternatively a compound of formula (III) may be prepared by reaction ofa compound of formula (VIIIA) or formula (VIIIB):

wherein R₁, R₂ and m are as hereinbefore defined for a compound offormula (I) and X is a leaving group as defined for compounds of formula(VI) with a compound of formula (VII).

For example a compound of formula (VIIIA), a compound of formula (VII)and a suitable base, for example triethylamine, are dissolved in asuitable solvent, for example acetontrile and heated at a suitabletemperature, for example 60-80° C. for a suitable period of time, forexample 16-26 hours. The product (III) is isolated after an aqueouswork-up and purification.

For example a suitable reducing agent, for example sodiumtriacetoxyborohydride, is added to a mixture of a compound of formula(VIIIB), a compound of formula (VII) and a drying agent, for example 4 Åmolecular sieves, in a suitable solvent, for example dichloromethane,and stirred at a suitable temperature, for example 20° C., for asuitable period of time, for example 1-2 hours. The product (III) isisolated after an aqueous work-up and purification.

Compounds of formula (VIIIA) can be prepared by reaction of compounds offormula (IV) with compounds of formula (VI). For example a compound offormula (IV), a compound of formula (VI) are dissolved in a suitablesolvent, for example N,N-dimethylformamide, in the presence of copper(I)iodide, a suitable catalyst, for examplebis(triphenylphosphine)palladium(II) dichloride and a suitable base, forexample triethylamine, and heated at a suitable temperature, for example20° C. for a suitable period of time, for example 18-20 hours. Theproduct (VIIIA) is isolated after an aqueous work-up and purification.

Compounds of formula (VIIIB) can be prepared by reaction of compounds offormula (IX):

wherein R₁, R₂ and m are as hereinbefore defined for a compound offormula (I) with an oxidising agent, for example tetrapropylammoniumperruthenate in the presence of 4-methylmorpholine N-oxide.

For example a compound of formula (IX), a suitable oxidant, for exampletetrapropylammonium perruthenate in the presence of 4-methylmorpholineN-oxide, in a suitable solvent, for example a mixture of dichloromethaneand acetonitrile, was stirred at a suitable temperature, for example 20°C., for a suitable period of time, for example 2 hours. The reactionmixture is filtered and the product (VIIIB) isolated by removal of thesolvent and purification if required.

Compounds of formula (IX) can be prepared by reaction of compounds offormula (IV) with appropriate alkyn-1-ols. For example a compound offormula (IV), the alkyn-1-ol are dissolved in a suitable solvent, forexample N,N-dimethylformamide, in the presence of copper(I) iodide, asuitable catalyst, for example bis(triphenylphosphine)palladium(II)dichloride and a suitable base, for example triethylamine, and heated ata suitable temperature, for example 20° C. for a suitable period oftime, for example 18-20 hours. The product (IX) is isolated after anaqueous work-up and purification.

Alternatively compounds of formula (II) may be prepared by reaction ofcompounds of formula (X):

wherein R₁, R₂ and m are as hereinbefore defined for a compound offormula (I)

For example a suitable reducing agent, for example sodiumtriacetoxyborohydride, is added to a mixture of a compound of formula(X), a compound of formula (VII) and a drying agent, for example 4 Åmolecular sieves, in a suitable solvent, for example dichloromethane,and stirred at a suitable temperature, for example 20° C., for asuitable period of time, for example 1-2 hours. The product (II) isisolated after an aqueous work-up and purification.

Compounds of formula (X) may be prepared by reaction of compounds offormula (XI):

wherein R₁, R₂ and m are as hereinbefore defined for a compound offormula (I)

For example a compound of formula (XI), a suitable oxidant, for exampletetrapropylammonium perruthenate in the presence of 4-methylmorpholineN-oxide, in a suitable solvent, for example a mixture of dichloromethaneand acetonitrile, was stirred at a suitable temperature, for example 20°C., for a suitable period of time, for example 2 hours. The product (X)isolated by removal of the solvent and purification if required.

Compounds of formula (XI) may be prepared by reaction of compounds offormula (IX) with hydrogen in the presence of a catalyst. For example acompound of formula (IX) is dissolved in a suitable solvent, for exampleethanol, and passed over a suitable catalyst, for example 10% palladiumon carbon in the presence of hydrogen, at a suitable temperature, forexample 20-60° C. in an apparatus such as the Thales H-cube™. Theproduct (XI) is isolated by removal of the solvent and purification ifrequired.

Compounds of formula (IV) may be prepared by reaction of compounds offormula (XII):

wherein R₁ and R₂ are as hereinbefore defined for a compound of formula(I) and Y is defined for a compound of formula (IV) with a solution ofammonia.

For example a solution of aqueous ammonia (0.88) is added to a solutionof a compound of formula (XII) in a suitable solvent, for exampleiso-propyl alcohol. The resultant mixture is then heated in a microwaveheater at a suitable temperature, for example 120-150° C. for a suitableperiod of time, for example 1-2 hours. The product (IV) is isolatedafter an aqueous work-up and purification.

Compounds of formula (XII) may be prepared by reaction of compounds offormula (XIII):

wherein R₁ and R₂ are as hereinbefore defined for a compound of formula(I) with a compound of formula (XIV):

wherein compound of formula (XIV) is a suitable precursor to theprotecting group PG, for example benzyl chloromethyl ether or(2-(chloromethoxy)ethyl)trimethylsilane.

For example, a compound of formula (XIII) in a suitable solvent, forexample N,N-dimethylformamide or tetrahydrofuran, is treated with asuitable base, for example a suspension of sodium hydride in oil. Acompound of formula (XIV), for example benzyl chloromethyl ether or(2-(chloromethoxy)ethyl)trimethylsilane is added and the reactionmixture is stirred at a suitable temperature, for example 20° C. for asuitable period of time, for example 1-4 hours. The product (XII) isisolated after an aqueous work-up and purification.

Compounds of formula (XIII) may be prepared by reaction of compounds offormula (XV):

wherein R₁ and R₂ are as hereinbefore defined for a compound of formula(I) with a halogenating reagent, for example N-iodosuccinimide.

For example a compound of formula (XV) is dissolved in a suitablesolvent, for example tetrahydrofuran, is reacted with N-iodosuccinimideat suitable temperature, for example 20° C. for a suitable period oftime, for example 1-2 hours. The product (XIII) is isolated after anaqueous work-up and purification.

Compounds of formula (XV) may be prepared by reaction of compounds offormula (XVI):

wherein R₁ and R₂ are as hereinbefore defined for a compound of formula(I) with a chlorinating reagent, for example phosphorus oxychloride.

For example a compound of formula (XVI) is suspended in phosphorusoxychloride and heated at a suitable temperature, for example 120° C.for a suitable period of time, for example 3-4 hours. Excess phosphorusoxychloride may be removed in vacuo then the residue is poured onto iceand the pH of the mixture adjusted to 7-9. The product is then extractedinto a suitable organic solvent, for example ethyl acetate. The product(XV) is isolated by removal of the solvent and purification if required.

Compounds of formula (XVI) may be prepared by reaction of compounds offormula (XVII):

wherein R₁ and R₂ are as hereinbefore defined for a compound of formula(I) with a suitable base, for example sodium hydroxide.

For example a solution of compounds of formula (XVII) in a suitablesolvent, for example ethyl alcohol, is treated with an aqueous solutionof sodium hydroxide and the reaction mixture stirred at a suitabletemperature, for example 80-100° C. for a suitable period of time, forexample 4-18 hours. The product (XVI) is isolated after an aqueouswork-up and purification.

Compounds of formula (XVII) can be prepared by reaction of compounds offormula (XVIII):

with compounds of formula (XIX):

wherein R₁ and R₂ are as hereinbefore defined for a compound of formula(I).

For example, a suspension of a compound of formula (XVIII) in a compoundof formula (XIX) is treated with a solution of hydrogen chloride in asuitable solvent, for example a solution of hydrogen chloride in1,4-dioxane and is heated at a suitable temperature, 50-70° C. for asuitable period of time, for example 16-18 hours. The product (XVIII) isisolated after filtration after the addition of a suitable solvent, forexample tert-butyl methyl ether.

Alternatively compound of formula (XVI) can be prepared by reaction ofcompounds of formula (XVIII) with compounds of formula (XX):

wherein R₁ is as hereinbefore defined for a compound of formula (I).

For example, a mixture of compounds of formula (XVIII) and compounds offormula (XX) are heated in a suitable solvent, for example o-xylene, ata suitable temperature, for example reflux, for a suitable period oftime, for example, 3 days. After cooling to ambient temperature theproduct (XVI) is isolated after filtration.

Compounds of formulae (VI), (VII), (XIV), (XVIII), (XIX) and (XX) areeither known in the literature or are commercially available, forexample from Sigma-Aldrich, UK, or may be prepared by analogy with knownprocedures, for example those disclosed in standard reference texts ofsynthetic methodology such as J. March, Advanced Organic Chemistry, 6thEdition (2007), WileyBlackwell, or Comprehensive Organic Synthesis(Trost B. M. and Fleming I., (Eds.), Pergamon Press, 1991), eachincorporated herein by reference as it relates to such procedures.

Examples of other protecting groups that may be employed in thesynthetic routes described herein and the means for their removal can befound in T. W. Greene ‘Protective Groups in Organic Synthesis’, 4thEdition, J. Wiley and Sons, 2006, incorporated herein by reference as itrelates to such procedures.

For any of the hereinbefore described reactions or processes,conventional methods of heating and cooling may be employed, for exampletemperature-regulated oil-baths or temperature-regulated hot-blocks, andice/salt baths or dry ice/acetone baths respectively. Conventionalmethods of isolation, for example extraction from or into aqueous ornon-aqueous solvents may be used. Conventional methods of drying organicsolvents, solutions, or extracts, such as shaking with anhydrousmagnesium sulphate, or anhydrous sodium sulphate, or passing through ahydrophobic frit, may be employed. Conventional methods of purification,for example crystallisation and chromatography, for example silicachromatography or reverse-phase chromatography, may be used as required.Crystallisation may be performed using conventional solvents such asethyl acetate, methanol, ethanol, or butanol, or aqueous mixturesthereof. It will be appreciated that specific reaction timestemperatures may typically be determined by reaction-monitoringtechniques, for example thin-layer chromatography and LC-MS.

Where appropriate individual isomeric forms of the compounds of theinvention may be prepared as individual isomers using conventionalprocedures such as the fractional crystallisation of diastereoisomericderivatives or chiral high performance liquid chromatography (chiralHPLC).

The absolute stereochemistry of compounds may be determined usingconventional methods, such as X-ray crystallography.

Methods of Use

Examples of disease states in which the compounds of formula (I) andpharmaceutically acceptable salts thereof have potentially beneficialeffects include allergic diseases and other inflammatory conditions forexample allergic rhinitis and asthma, infectious diseases, and cancer.

As modulators of the immune response the compounds of formula (I) andpharmaceutically acceptable salts thereof may also be useful in thetreatment and/or prevention of immune-mediated disorders, including butnot limited to inflammatory or allergic diseases such as asthma,allergic rhinitis and rhinoconjuctivitis, food allergy, hypersensitivitylung diseases, eosinophilic pneumonitis, delayed-type hypersensitivitydisorders, atherosclerosis, pancreatitis, gastritis, colitis,osteoarthritis, psoriasis, sarcoidosis, pulmonary fibrosis, respiratorydistress syndrome, bronchiolitis, chronic obstructive pulmonary disease,sinusitis, cystic fibrosis, actinic keratosis, skin dysplasia, chronicurticaria, eczema and all types of dermatitis.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may also be useful in the treatment and/or prevention ofreactions against respiratory infections, including but not limited toairways viral exacerbations and tonsillitis. The compounds may also beuseful in the treatment and/or prevention of autoimmune diseasesincluding but not limited to rheumatoid arthritis, psoriatic arthritis,systemic lupus erythematosus, Sjöegrens disease, ankylosing spondylitis,scleroderma, dermatomyositis, diabetes, graft rejection, includinggraft-versus-host disease, inflammatory bowel diseases including, butnot limited to, Crohn's disease and ulcerative colitis.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may also be useful in the treatment of infectious diseasesincluding, but not limited to, those caused by hepatitis viruses (e.g.hepatitis B virus, hepatitis C virus), human immunodeficiency virus,papillomaviruses, herpesviruses, respiratory viruses (e.g. influenzaviruses, respiratory syncytial virus, rhinovirus, metapneumovirus,parainfluenzavirus, SARS), and West Nile virus. The compounds of formula(I) and pharmaceutically acceptable salts thereof may also be useful inthe treatment of microbial infections caused by, for example, bacteria,fungi, or protozoa. These include, but are not limited to, tuberculosis,bacterial pneumonia, aspergillosis, histoplasmosis, candidosis,pneumocystosis, leprosy, chlamydia, cryptococcal disease,cryptosporidosis, toxoplasmosis, leishmania, malaria, andtrypanosomiasis.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may also be useful in the treatment of various cancers, inparticular the treatment of cancers that are known to be responsive toimmunotherapy and including, but not limited to, renal cell carcinoma,lung cancer, breast cancer, colorectal cancer, bladder cancer, melanoma,leukaemia, lymphomas and ovarian cancer.

It will be appreciated by those skilled in the art that referencesherein to treatment or therapy may, depending on the condition, extendto prophylaxis as well as the treatment of established conditions.

There is thus provided as a further aspect of the invention a compoundof formula (I), or a pharmaceutically acceptable salt thereof, for usein therapy.

It will be appreciated that, when a compound of formula (I) or apharmaceutically acceptable salt thereof is used in therapy, it is usedas an active therapeutic agent.

There is also therefore provided a compound of formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofallergic diseases and other inflammatory conditions, infectiousdiseases, and cancer.

There is also therefore provided a compound of formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofallergic rhinitis.

There is also therefore provided a compound of formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofasthma.

There is further provided the use of a compound of formula (I), or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of allergic diseases and other inflammatoryconditions, infectious diseases, and cancer.

There is further provided the use of a compound of formula (I), or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of allergic rhinitis.

There is further provided the use of a compound of formula (I), or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of asthma.

There is further provided a method of treatment of allergic diseases andother inflammatory conditions, infectious diseases, and cancer, whichmethod comprises administering to a human subject in need thereof, atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof.

There is further provided a method of treatment of allergic rhinitis,which method comprises administering to a human subject in need thereof,a therapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof.

There is further provided a method of treatment of asthma, which methodcomprises administering to a human subject in need thereof, atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof are also of potential use as vaccine adjuvants.

There is thus provided as a further aspect of the invention a vaccinecomposition comprising a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, and an antigen or antigen composition for usein therapy.

There is thus provided as a further aspect of the invention the use of acompound of formula (I), or a pharmaceutically acceptable salt thereof,and an antigen or antigen composition in the manufacture of a medicamentfor use in therapy.

There is further provided a method of treating or preventing diseasecomprising the administration to a human subject suffering from orsusceptible to disease, a vaccine composition comprising a compound offormula (I), or a pharmaceutically acceptable salt thereof, and anantigen or antigen composition.

Compositions

The compounds of formula (I) and pharmaceutically acceptable saltsthereof will normally, but not necessarily, be formulated intopharmaceutical compositions prior to administration to a patient.Accordingly, in another aspect of the invention there is provided apharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may be formulated for administration in any convenient way. Thecompounds of formula (I) and pharmaceutically acceptable salts thereofmay, for example, be formulated for oral, topical, inhaled, intranasal,buccal, parenteral (for example intravenous, subcutaneous, intradermal,or intramuscular) or rectal administration. In one aspect, the compoundsof formula (I) and pharmaceutically acceptable salts thereof areformulated for oral administration. In a further aspect, the compoundsof formula (I) and pharmaceutically acceptable salts thereof areformulated for topical administration, for example intranasal or inhaledadministration.

Tablets and capsules for oral administration may contain conventionalexcipients such as binding agents, for example syrup, acacia, gelatin,sorbitol, tragacanth, mucilage of starch, cellulose or polyvinylpyrrolidone; fillers, for example, lactose, microcrystalline cellulose,sugar, maize starch, calcium phosphate or sorbitol; lubricants, forexample, magnesium stearate, stearic acid, talc, polyethylene glycol orsilica; disintegrants, for example, potato starch, croscarmellose sodiumor sodium starch glycollate; or wetting agents such as sodium laurylsulphate. The tablets may be coated according to methods well known inthe art.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations may contain conventionaladditives such as suspending agents, for example, sorbitol syrup, methylcellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats; emulsifying agents, for example, lecithin, sorbitan mono-oleate oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, fractionated coconut oil, oily esters, propyleneglycol or ethyl alcohol; or preservatives, for example, methyl or propylp-hydroxybenzoates or sorbic acid. The preparations may also containbuffer salts, flavouring, colouring and/or sweetening agents (e.g.mannitol) as appropriate.

Compositions for intranasal administration include aqueous compositionsadministered to the nose by drops or by pressurised pump. Suitablecompositions contain water as the diluent or carrier for this purpose.Compositions for administration to the lung or nose may contain one ormore excipients, for example one or more suspending agents, one or morepreservatives, one or more surfactants, one or more tonicity adjustingagents, one or more co-solvents, and may include components to controlthe pH of the composition, for example a buffer system. Further, thecompositions may contain other excipients such as antioxidants, forexample sodium metabisulphite, and taste-masking agents. Compositionsmay also be administered to the nose or other regions of the respiratorytract by nebulisation.

Intranasal compositions may permit the compound(s) of formula (I) or (a)pharmaceutically acceptable salt(s) thereof to be delivered to all areasof the nasal cavities (the target tissue) and further, may permit thecompound(s) of formula (I) or (a) pharmaceutically acceptable salt(s)thereof to remain in contact with the target tissue for longer periodsof time. A suitable dosing regime for intranasal compositions would befor the patient to inhale slowly through the nose subsequent to thenasal cavity being cleared. During inhalation the composition would beadministered to one nostril while the other is manually compressed. Thisprocedure would then be repeated for the other nostril. Typically, oneor two sprays per nostril would be administered by the above procedureone, two, or three times each day, ideally once daily. Of particularinterest are intranasal compositions suitable for once-dailyadministration.

The suspending agent(s), if included, will typically be present in anamount of from 0.1 to 5% (w/w), such as from 1.5% to 2.4% (w/w), basedon the total weight of the composition. Examples of pharmaceuticallyacceptable suspending agents include, but are not limited to, Avicel®(microcrystalline cellulose and carboxymethylcellulose sodium),carboxymethylcellulose sodium, veegum, tragacanth, bentonite,methylcellulose, xanthan gum, carbopol and polyethylene glycols.

Compositions for administration to the lung or nose may contain one ormore excipients may be protected from microbial or fungal contaminationand growth by inclusion of one or more preservatives. Examples ofpharmaceutically acceptable anti-microbial agents or preservativesinclude, but are not limited to, quaternary ammonium compounds (forexample benzalkonium chloride, benzethonium chloride, cetrimide,cetylpyridinium chloride, lauralkonium chloride and myristyl picoliniumchloride), mercurial agents (for example phenylmercuric nitrate,phenylmercuric acetate and thimerosal), alcoholic agents (for examplechlorobutanol, phenylethyl alcohol and benzyl alcohol), antibacterialesters (for example esters of para-hydroxybenzoic acid), chelatingagents such as disodium edetate (EDTA) and other anti-microbial agentssuch as chlorhexidine, chlorocresol, sorbic acid and its salts (such aspotassium sorbate) and polymyxin. Examples of pharmaceuticallyacceptable anti-fungal agents or preservatives include, but are notlimited to, sodium benzoate, sorbic acid, sodium propionate,methylparaben, ethylparaben, propylparaben and butylparaben. Thepreservative(s), if included, may be present in an amount of from 0.001to 1% (w/w), such as from 0.015% to 0.5% (w/w) based on the total weightof the composition.

Compositions (for example wherein at least one compound is insuspension) may include one or more surfactants which functions tofacilitate dissolution of the medicament particles in the aqueous phaseof the composition. For example, the amount of surfactant used is anamount which will not cause foaming during mixing. Examples ofpharmaceutically acceptable surfactants include fatty alcohols, estersand ethers, such as polyoxyethylene (20) sorbitan monooleate(Polysorbate 80), macrogol ethers, and poloxamers. The surfactant may bepresent in an amount of between about 0.01 to 10% (w/w), such as from0.01 to 0.75% (w/w), for example about 0.5% (w/w), based on the totalweight of the composition.

One or more tonicity-adjusting agent(s) may be included to achievetonicity with body fluids e.g. fluids of the nasal cavity, resulting inreduced levels of irritancy. Examples of pharmaceutically acceptabletonicity-adjusting agents include, but are not limited to, sodiumchloride, dextrose, xylitol, calcium chloride, glucose, glycerine andsorbitol. A tonicity-adjusting agent, if present, may be included in anamount of from 0.1 to 10% (w/w), such as from 4.5 to 5.5% (w/w), forexample about 5.0% (w/w), based on the total weight of the composition.

The compositions of the invention may be buffered by the addition ofsuitable buffering agents such as sodium citrate, citric acid,trometamol, phosphates such as disodium phosphate (for example thedodecahydrate, heptahydrate, dihydrate and anhydrous forms), or sodiumphosphate and mixtures thereof.

A buffering agent, if present, may be included in an amount of from 0.1to 5% (w/w), for example 1 to 3% (w/w) based on the total weight of thecomposition.

Examples of taste-masking agents include sucralose, sucrose, saccharinor a salt thereof, fructose, dextrose, glycerol, corn syrup, aspartame,acesulfame-K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate,thaumatin, neotame, mannitol, menthol, eucalyptus oil, camphor, anatural flavouring agent, an artificial flavouring agent, andcombinations thereof.

One or more co-solvent(s) may be included to aid solubility of themedicament compound(s) and/or other excipients. Examples ofpharmaceutically acceptable co-solvents include, but are not limited to,propylene glycol, dipropylene glycol, ethylene glycol, glycerol,ethanol, polyethylene glycols (for example PEG300 or PEG400), andmethanol. In one embodiment, the co-solvent is propylene glycol.

Co-solvent(s), if present, may be included in an amount of from 0.05 to30% (w/w), such as from 1 to 25% (w/w), for example from 1 to 10% (w/w)based on the total weight of the composition.

Compositions for inhaled administration include aqueous, organic oraqueous/organic mixtures, dry powder or crystalline compositionsadministered to the respiratory tract by pressurised pump or inhaler,for example, reservoir dry powder inhalers, unit-dose dry powderinhalers, pre-metered multi-dose dry powder inhalers, nasal inhalers orpressurised aerosol inhalers, nebulisers or insufflators. Suitablecompositions contain water as the diluent or carrier for this purposeand may be provided with conventional excipients such as bufferingagents, tonicity modifying agents and the like. Aqueous compositions mayalso be administered to the nose and other regions of the respiratorytract by nebulisation. Such compositions may be aqueous solutions orsuspensions or aerosols delivered from pressurised packs, such as ametered dose inhaler, with the use of a suitable liquefied propellant.

Compositions for administration topically to the nose (for example, forthe treatment of rhinitis) or to the lung, include pressurised aerosolcompositions and aqueous compositions delivered to the nasal cavities bypressurised pump. Compositions which are non-pressurised and aresuitable for administration topically to the nasal cavity are ofparticular interest. Suitable compositions contain water as the diluentor carrier for this purpose. Aqueous compositions for administration tothe lung or nose may be provided with conventional excipients such asbuffering agents, tonicity-modifying agents and the like. Aqueouscompositions may also be administered to the nose by nebulisation.

A fluid dispenser may typically be used to deliver a fluid compositionto the nasal cavities. The fluid composition may be aqueous ornon-aqueous, but typically aqueous. The compound of formula (I), or apharmaceutically acceptable salt thereof, may be formulated as asuspension or solution. Such a fluid dispenser may have a dispensingnozzle or dispensing orifice through which a metered dose of the fluidcomposition is dispensed upon the application of a user-applied force toa pump mechanism of the fluid dispenser. Such fluid dispensers aregenerally provided with a reservoir of multiple metered doses of thefluid composition, the doses being dispensable upon sequential pumpactuations. Alternatively, the fluid dispenser for delivery of a fluidcomposition to the nasal cavities may be designed to be dose-limited,for example a single use dispenser comprising a single dose. Thedispensing nozzle or orifice may be configured for insertion into thenostrils of the user for spray dispensing of the fluid composition intothe nasal cavity. A fluid dispenser of the aforementioned type isdescribed and illustrated in International Patent Applicationpublication number WO 2005/044354 (Glaxo Group Limited). The dispenserhas a housing which houses a fluid-discharge device having a compressionpump mounted on a container for containing a fluid composition. Thehousing has at least one finger-operable side lever which is movableinwardly with respect to the housing to move the container upwardly inthe housing by means of a cam to cause the pump to compress and pump ametered dose of the composition out of a pump stem through a nasalnozzle of the housing. In one embodiment, the fluid dispenser is of thegeneral type illustrated in FIGS. 30-40 of WO 2005/044354.

Aqueous compositions containing a compound of formula (I) or apharmaceutically acceptable salt thereof may also be delivered by a pumpas disclosed in International Patent Application publication numberWO2007/138084 (Glaxo Group Limited), for example as disclosed withreference to FIGS. 22-46 thereof, or as disclosed in United Kingdompatent application number GB0723418.0 (Glaxo Group Limited), for exampleas disclosed with reference to FIGS. 7-32 thereof. The pump may beactuated by an actuator as disclosed in FIGS. 1-6 of GB0723418.0.

Dry powder compositions for topical delivery to the lung by inhalationmay, for example, be presented in capsules and cartridges of for examplegelatine, or blisters of for example laminated aluminium foil, for usein an inhaler or insufflator. Powder blend compositions generallycontain a powder mix for inhalation of the compound of formula (I) or apharmaceutically acceptable salt thereof and a suitable powder base(carrier/diluent/excipient substance) such as mono-, di-, orpolysaccharides (for example lactose or starch). Dry powder compositionsmay also include, in addition to the drug and carrier, a furtherexcipient (for example a ternary agent such as a sugar ester for examplecellobiose octaacetate, calcium stearate, or magnesium stearate.

In one embodiment, a composition suitable for inhaled administration maybe incorporated into a plurality of sealed dose containers provided onmedicament pack(s) mounted inside a suitable inhalation device. Thecontainers may be rupturable, peelable, or otherwise openableone-at-a-time and the doses of the dry powder composition administeredby inhalation on a mouthpiece of the inhalation device, as known in theart. The medicament pack may take a number of different forms, forinstance a disk-shape or an elongate strip. Representative inhalationdevices are the DISKHALER™ and DISKUS™ devices, marketed byGlaxoSmithKline.

A dry powder inhalable composition may also be provided as a bulkreservoir in an inhalation device, the device then being provided with ametering mechanism for metering a dose of the composition from thereservoir to an inhalation channel where the metered dose is able to beinhaled by a patient inhaling at a mouthpiece of the device. Exemplarymarketed devices of this type are TURBUHALER™ (AstraZeneca), TWISTHALER™(Schering) and CLICKHALER™ (Innovata.)

A further delivery method for a dry powder inhalable composition is formetered doses of the composition to be provided in capsules (one doseper capsule) which are then loaded into an inhalation device, typicallyby the patient on demand. The device has means to rupture, pierce orotherwise open the capsule so that the dose is able to be entrained intothe patient's lung when they inhale at the device mouthpiece. Asmarketed examples of such devices there may be mentioned ROTAHALER™(GlaxoSmithKline) and HANDIHALER™ (Boehringer Ingelheim.)

Pressurised aerosol compositions suitable for inhalation can be either asuspension or a solution and may contain a compound of formula (I) or apharmaceutically acceptable salt thereof and a suitable propellant suchas a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixturesthereof, particularly hydrofluoroalkanes, especially1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or amixture thereof. The aerosol composition may optionally containadditional composition excipients well known in the art such assurfactants e.g. oleic acid, lecithin or an oligolactic acid orderivative thereof e.g. as described in WO 94/21229 and WO 98/34596(Minnesota Mining and Manufacturing Company) and co-solvents e.g.ethanol. Pressurised compositions will generally be retained in acanister (e.g. an aluminium canister) closed with a valve (e.g. ametering valve) and fitted into an actuator provided with a mouthpiece.

Ointments, creams and gels, may, for example, be formulated with anaqueous or oily base with the addition of suitable thickening and/orgelling agent and/or solvents. Such bases may thus, for example, includewater and/or an oil such as liquid paraffin or a vegetable oil such asarachis oil or castor oil, or a solvent such as polyethylene glycol.Thickening agents and gelling agents which may be used according to thenature of the base include soft paraffin, aluminium stearate,cetostearyl alcohol, polyethylene glycols, wool-fat, beeswax,carboxypolymethylene and cellulose derivatives, and/or glycerylmonostearate and/or non-ionic emulsifying agents.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents or thickening agents.

Powders for external application may be formed with the aid of anysuitable powder base, for example, talc, lactose or starch. Drops may beformulated with an aqueous or non-aqueous base also comprising one ormore dispersing agents, solubilising agents, suspending agents orpreservatives.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may, for example, be formulated for transdermal delivery bycomposition into patches or other devices (e.g. pressurised gas devices)which deliver the active component into the skin. For buccaladministration the compositions may take the form of tablets or lozengesformulated in the conventional manner.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may also be formulated as suppositories, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may also be formulated for parenteral administration by bolusinjection or continuous infusion and may be presented in unit dose form,for instance as ampoules, vials, small volume infusions or pre-filledsyringes, or in multidose containers with an added preservative. Thecompositions may take such forms as solutions, suspensions, or emulsionsin aqueous or non-aqueous vehicles, and may contain formulatory agentssuch as anti-oxidants, buffers, antimicrobial agents and/or tonicityadjusting agents. Alternatively, the active ingredient may be in powderform for constitution with a suitable vehicle, e.g. sterile,pyrogen-free water, before use. The dry solid presentation may beprepared by filling a sterile powder aseptically into individual sterilecontainers or by filling a sterile solution aseptically into eachcontainer and freeze-drying.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may also be formulated with vaccines as adjuvants to modulatetheir activity. Such compositions may contain antibody(ies) or antibodyfragment(s) or an antigenic component including but not limited toprotein, DNA, live or dead bacteria and/or viruses or virus-likeparticles, together with one or more components with adjuvant activityincluding but not limited to aluminium salts, oil and water emulsions,heat shock proteins, lipid A preparations and derivatives, glycolipids,other TLR agonists such as CpG DNA or similar agents, cytokines such asGM-CSF or IL-12 or similar agents.

In a further aspect of the invention, there is provided a vaccineadjuvant comprising a compound of formula (I), or a pharmaceuticallyacceptable salt thereof.

There is further provided a vaccine composition comprising a compound offormula (I), or a pharmaceutically acceptable salt thereof, and anantigen or antigen composition.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may be employed alone or in combination with othertherapeutically-active agents. The invention provides in a furtheraspect, a combination comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, together with at least oneother therapeutically-active agent.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof and the other therapeutically-active agent(s) may beadministered together or separately and, when administered separately,administration may occur simultaneously or sequentially, in any order.The amounts of the compound(s) of formula (I) or (a) pharmaceuticallyacceptable salt(s) thereof and the other therapeutically-active agent(s)and the relative timings of administration will be selected in order toachieve the desired combined therapeutic effect. The administration of acombination of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof with other treatment agents may be byadministration concomitantly in a unitary pharmaceutical compositionincluding both compounds, or in separate pharmaceutical compositionseach including one of the compounds. Alternatively, the combination maybe administered separately in a sequential manner wherein one treatmentagent is administered first and the other second or vice versa. Suchsequential administration may be close in time or remote in time.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may be used in combination with one or more agents useful in theprevention or treatment of viral infections. Examples of such agentsinclude, without limitation; polymerase inhibitors such as thosedisclosed in WO 2004/037818-A1, as well as those disclosed in WO2004/037818 and WO 2006/045613; JTK-003, JTK-019, NM-283, HCV-796,R-803, R1728, R1626, as well as those disclosed in WO 2006/018725, WO2004/074270, WO 2003/095441, US2005/0176701, WO 2006/020082, WO2005/080388, WO 2004/064925, WO 2004/065367, WO 2003/007945, WO02/04425, WO 2005/014543, WO 2003/000254, EP 1065213, WO 01/47883, WO2002/057287, WO 2002/057245 and similar agents; replication inhibitorssuch as acyclovir, famciclovir, ganciclovir, cidofovir, lamivudine andsimilar agents; protease inhibitors such as the HIV protease inhibitorssaquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir,brecanavir, atazanavir, tipranavir, palinavir, lasinavir, and the HCVprotease inhibitors BILN2061, VX-950, SCH503034; and similar agents;nucleoside and nucleotide reverse transcriptase inhibitors such aszidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavidine,adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine,alovudine, amdoxovir, elvucitabine, and similar agents; non-nucleosidereverse transcriptase inhibitors (including an agent havinganti-oxidation activity such as immunocal, oltipraz etc.) such asnevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz,capravirine, TMC-278, TMC-125, etravirine, and similar agents; entryinhibitors such as enfuvirtide (T-20), T-1249, PRO-542, PRO-140,TNX-355, BMS-806, 5-Helix and similar agents; integrase inhibitors suchas L-870,180 and similar agents; budding inhibitors such as PA-344 andPA-457, and similar agents; chemokine receptor inhibitors such asvicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK-427,857), TAK449, aswell as those disclosed in WO 02/74769, WO 2004/054974, WO 2004/055012,WO 2004/055010, WO 2004/055016, WO 2004/055011, and WO 2004/054581, andsimilar agents; neuraminidase inhibitors such as CS-8958, zanamivir,oseltamivir, peramivir and similar agents; ion channel blockers such asamantadine or rimantadine and similar agents; and interfering RNA andantisense oligonucleotides and such as ISIS-14803 and similar agents;antiviral agents of undetermined mechanism of action, for example thosedisclosed in WO 2005/105761, WO 2003/085375, WO 2006/122011, ribavirin,and similar agents. The compounds of formula (I) and pharmaceuticallyacceptable salts thereof may also be used in combination with one ormore other agents which may be useful in the prevention or treatment ofviral infections for example immune therapies (e.g. interferon or othercytokines/chemokines, cytokine/chemokine receptor modulators, cytokineagonists or antagonists and similar agents); and therapeutic vaccines,antifibrotic agents, anti-inflammatory agents such as corticosteroids orNSAIDs (non-steroidal anti-inflammatory agents) and similar agents.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may be used in combination with one or more other agents whichmay be useful in the prevention or treatment of allergic disease,inflammatory disease, autoimmune disease, for example; antigenimmunotherapy, anti-histamines, steroids, NSAIDs, bronchodilators (e.g.beta 2 agonists, adrenergic agonists, anticholinergic agents,theophylline), methotrexate, leukotriene modulators and similar agents;monoclonal antibody therapy such as anti-IgE, anti-TNF, anti-IL-5,anti-IL-6, anti-IL-12, anti-IL-1 and similar agents; receptor therapiese.g. entanercept and similar agents; antigen non-specificimmunotherapies (e.g. interferon or other cytokines/chemokines,cytokine/chemokine receptor modulators, cytokine agonists orantagonists, TLR agonists and similar agents).

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may be used in combination with one or more other agents whichmay be useful in the prevention or treatment of cancer, for examplechemotherapeutics such as alkylating agents, topoisomerase inhibitors,antimetabolites, antimitotic agents, kinase inhibitors and similaragents; monoclonal antibody therapy such as trastuzumab, gemtuzumab andother similar agents; and hormone therapy such as tamoxifen, goserelinand similar agents.

The pharmaceutical compositions according to the invention may also beused alone or in combination with at least one other therapeutic agentin other therapeutic areas, for example gastrointestinal disease. Thecompositions according to the invention may also be used in combinationwith gene replacement therapy.

The invention includes in a further aspect a combination comprising acompound of formula (I), or a pharmaceutically acceptable salt thereof,together with at least one other therapeutically active agent.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical composition and thus pharmaceuticalcompositions comprising a combination as defined above together with atleast one pharmaceutically acceptable diluent or carrier thereofrepresent a further aspect of the invention.

A therapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof will depend upon a number offactors. For example, the species, age, and weight of the recipient, theprecise condition requiring treatment and its severity, the nature ofthe composition, and the route of administration are all factors to beconsidered. The therapeutically effective amount ultimately should be atthe discretion of the attendant physician. Regardless, an effectiveamount of a compound of the present invention for the treatment ofhumans suffering from frailty, generally, should be in the range of0.0001 to 100 mg/kg body weight of recipient per day. More usually theeffective amount should be in the range of 0.001 to 10 mg/kg body weightper day. Thus, for a 70 kg adult one example of an actual amount per daywould usually be from 7 to 700 mg. For intranasal and inhaled routes ofadministration, typical doses for a 70 kg adult should be in the rangeof 0.1 micrograms to 1 mg per day, for example 1 μg, 10 μg or 100 μg.This amount may be given in a single dose per day or in a number (suchas two, three, four, five, or more) of sub-doses per day such that thetotal daily dose is the same. An effective amount of a pharmaceuticallyacceptable salt of a compound of formula (I) may be determined as aproportion of the effective amount of the compound of formula (I) or apharmaceutically acceptable salt thereof per se. Similar dosages shouldbe appropriate for treatment of the other conditions referred to herein.

Compounds of formula (I) and pharmaceutically acceptable salts thereofmay also be administered at any appropriate frequency e.g. 1-7 times perweek. The precise dosing regimen will of course depend on factors suchas the therapeutic indication, the age and condition of the patient, andthe particular route of administration chosen. In one aspect of theinvention, a compound of formula (I), or a pharmaceutically acceptablesalt thereof, may be administered once weekly for a period of 4 to 8weeks, for example 4, 5, 6, 7 or 8 weeks.

Pharmaceutical compositions may be presented in unit-dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, as a non-limiting example, 0.5 mg to 1 g of acompound of formula (I) or a pharmaceutically acceptable salt thereof,depending on the condition being treated, the route of administration,and the age, weight, and condition of the patient. Preferred unit-dosagecompositions are those containing a daily dose or sub-dose, as hereinabove recited, or an appropriate fraction thereof, of an activeingredient. Such pharmaceutical compositions may be prepared by any ofthe methods well-known in the pharmacy art.

There is also provided a process for preparing such a pharmaceuticalcomposition which comprises admixing a compound of formula (I), or apharmaceutically acceptable salt thereof, with one or morepharmaceutically acceptable excipients.

The compounds of formula (I) and salts thereof may be prepared by themethodology described hereinafter, constituting further aspects of thisinvention.

Aspects of the invention are illustrated by reference to, but are in noway limited by, the following Examples.

Analytical Methodology ¹H NMR

¹H NMR spectra were recorded in either CDCl₃ or DMSO-d₆ on either aBruker DPX 400 or Bruker Avance DRX, Varian Unity 400 spectrometer orJEOL Delta all working at 400 MHz. The internal standard used was eithertetramethylsilane or the residual protonated solvent at 7.25 ppm forCDCl₃ or 2.50 ppm for DMSO-d₆.

LCMS System A

Column: 50 mm×2.1 mm ID, 1.7 μm Acquity UPLC BEH C₁₈

Flow Rate: 1 mL/min.

Temp: 40° C.

UV detection range: 210 to 350 nm

Mass spectrum: Recorded on a mass spectrometer using alternative-scanpositive and negative mode electrospray ionisation

Solvents:

-   -   A: 0.1% v/v formic acid in water    -   B: 0.1% v/v formic acid acetonitrile

Time (min.) A % B % Gradient: 0 97 3 1.5 0 100 1.9 0 100 2.0 97 3

System B

Column: 50 mm×2.1 mm ID, 1.7 μm Acquity UPLC BEH C₁₈

Flow Rate: 1 mL/min.

Temp: 40° C.

UV detection range: 210 to 350 nm

Mass spectrum: Recorded on a mass spectrometer using alternative-scanpositive and negative mode electrospray ionisation

Solvents:

-   -   A: 10 mM ammonium bicarbonate in water adjusted to pH10 with        ammonia solution    -   B: acetonitrile

Time (min.) A % B % Gradient: 0 99 1 1.5 3 97 1.9 3 97 2.0 0 100

Mass Directed Autopreparative HPLC (MDAP)

Mass directed autopreparative HPLC was undertaken under the conditionsgiven below. The UV detection was an averaged signal from wavelength of210 nm to 350 nm and mass spectra were recorded on a mass spectrometerusing alternate-scan positive and negative mode electrospray ionization.

Method A

Method A was conducted on a Sunfire C₁₈ column (typically 150 mm×30 mmi.d. 5 μm packing diameter) at ambient temperature. The solventsemployed were:

A=0.1% v/v solution of formic acid in waterB=0.1% v/v solution of formic acid in acetonitrile.

Method B

Method B was conducted on an XBridge C₁₈ column (typically 100 mm×30 mmi.d. 5 μm packing diameter) at ambient temperature. The solventsemployed were:

A=10 mM aqueous ammonium bicarbonate adjusted to pH 10 with ammoniasolution.B=acetonitrile.

Method C

Method C was conducted on a Sunfire C₁₈ column (typically 150 mm×30 mmi.d. 5 μm packing diameter) at ambient temperature. The solventsemployed were:

A=0.1% v/v solution of trifluoroacetic acid in waterB=0.1% v/v solution of trifluoroacetic acid in acetonitrile.

Abbreviations

The following list provides definitions of certain abbreviations as usedherein. It will be appreciated that the list is not exhaustive, but themeaning of those abbreviations not herein below defined will be readilyapparent to those skilled in the art.

DCM Dichloromethane DMF N, N-Dimethylformamide DMSO DimethylsulphoxideTHF Tetrahydrofuran

EtOAc Ethyl acetate

MeOH Methanol EtOH Ethanol MeCN Acetonitrile

HCl Hydrochloric acidHPLC High performance liquid chromatography

MDAP Mass Directed Autopreparative HPLC

SPE Solid phase extraction

MeOH Methanol

TBME tert-Butyl methy etherTFA Trifluoroacetic acid

DIPEA N, N-Diisopropylethylamine Reaction Intermediates Intermediate 1:Ethyl 3-pentanimidamido-1H-pyrrole-2-carboxylate hydrochloride

A solution of hydrogen chloride in dioxane (12 mL, 4M, 48 mmol) wasadded dropwise to a suspension of ethyl 3-amino-1H-pyrrole-2-carboxylatehydrochloride (2.04 g, 10.7 mmol) (J. Org. Chem. 1999, 64(22), 8411) invaleronitrile (30 mL). The resultant mixture was heated at 50° C. for 18hours. The reaction mixture was cooled to room temperature and the solidmaterial collected by filtration and washed with TBME. The titlecompound was obtained as an off-white solid (2.19 g). A further portionof TBME was added to the filtrate and the mixture re-filtered, theprecipitate was washed with TBME and dried to give an additional portionof the title compound (0.275 g).

¹H NMR (400 MHz, DMSO-d₆) □ ppm 12.22 (br. s., 1H) 10.88 (s, 1H) 9.39(br. s, 1H) 8.25 (br. s, 1H) 7.09 (t, J=2.9 Hz, 1H) 6.19 (t, J=2.5 Hz,1H) 4.23 (q, J=7.0 Hz, 2H) 2.52-2.60 (m, 2H) 1.63-1.77 (m, 2H) 1.34-1.47(m, 2H) 1.27 (t, J=7.2 Hz, 3H) 0.94 (t, J=7.4 Hz, 3H)

Intermediate 2: 2-Butyl-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one

A solution of sodium hydroxide (1.44 g, 35.9 mmol) in water (7 mL) wasadded to a solution of ethyl 3-pentanimidamido-1H-pyrrole-2-carboxylatehydrochloride (2.46 g, 8.99 mmol) in ethanol (30 mL). The resultantmixture was heated at reflux for a total of 4 hours. The reactionmixture was cooled to room temperature and the pH adjusted to pH 6.5with aqueous citric acid. The resultant mixture was extracted with ethylacetate (2×50 mL). The combined organic phases were washed withsaturated aqueous sodium chloride solution, dried (Na₂SO₄), filtered andevaporated to give the title compound as a pale brown solid (1.69 g).

LCMS (System B): t_(RET)=0.66 min; MH⁺ 192

Intermediate 3: 2-Butyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidine

Phosphorus oxychloride (20 mL, 21.46 mmol) was added to2-butyl-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (1.69 g). The resultantmixture was heated at 100° C. After 4 hours the reaction mixture wascooled to room temperature then poured onto ice. The aqueous phase wastreated with aqueous sodium hydroxide solution (5M) until the pH was 7.The resultant mixture was extracted with ethyl acetate (2×150 ml). Thecombined organic phase were washed with brine, dried (Na₂SO₄), filteredand evaporated to give the title compound (1.69 g).

LCMS (System B): t_(RET)=0.90 min; MH⁺ 210, 212

Intermediate 4: 2-Butyl-4-chloro-7-iodo-5H-pyrrolo[3,2-d]pyrimidine

N-Iodosuccinimide (2.09 g, 9.29 mmol) was added portionwise to a stirredsolution of 2-butyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.69 g, 8.06mmol) in THF (35 mL). The resultant mixture was stirred at roomtemperature for 1 hour. The reaction mixture was diluted with TBME (50mL) then washed with aqueous sodium thiosulphate solution (50 mL) thensaturated aqueous sodium chloride solution (20 mL). The organic phasewas dried (Na₂SO₄), filtered and evaporated. The sample was dissolved indichloromethane and purified by chromatography on silica using agradient of 0-100% dichloromethane-cyclohexane over 30 mins followed bya gradient of 0-100% TBME-cyclohexane followed by 0-20% methanol over 15minutes. The appropriate fractions were identified by LC-MS thencombined and evaporated in vacuo to give the title compound as a yellowsolid (2.2 g).

LCMS (System B): t_(RET)=1.14 min; MH⁺ 336, 338

Intermediate 5:5-((Benzyloxy)methyl)-2-butyl-4-chloro-7-iodo-5H-pyrrolo[3,2-d]pyrimidine

Sodium hydride (0.338 g, 60% in oil, 14.08 mmol) was added portionwiseto a stirred solution of4-chloro-7-iodo-2-butyl-5H-pyrrolo[3,2-d]pyrimidine (2.19 g, 6.53 mmol)in DMF (30 mL) cooled in an ice-bath. After 30 minutes benzylchloromethyl ether (1.13 mL, 1.278 g, 8.16 mmol) was added and thereaction stirred at room temperature. The reaction mixture was quenchedwith water and the resultant mixture partitioned between ethyl acetate(150 mL) and water (150 mL). The organic phase was washed with waterthen saturated aqueous sodium chloride solution, dried (Na₂SO₄),filtered and evaporated. The sample was dissolved in dichloromethane andpurified by chromatography on silica (100 g) using a gradient of 0-100%ethyl acetate-cyclohexane over 30 mins. The appropriate fractions werecombined and evaporated in vacuo to give the title compound as a yellowoil (2.82 g).

LCMS (System B): t_(RET)=1.49 min; MH⁺ 456, 458

Intermediate 6:5-((Benzyloxy)methyl)-2-butyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amine

5-((Benzyloxy)methyl)-2-butyl-4-chloro-7-iodo-5H-pyrrolo[3,2-d]pyrimidine(1 g, 2.2 mmol) was suspended in 2-propanol (5 mL) and 35% (0.88)ammonia solution (4 mL). The reaction was stirred at 120° C. for 90minutes in a Biotage Initiator microwave. A further 1 mL of 35% (0.88)ammonia solution was added to the reaction. The reaction was stirred at120° C. for 90 minutes in a Biotage Initiator microwave. The reactionwas evaporated in vacuo to yield a pale yellow oil. The oil wasdissolved in the minimum volume of 20% methanol in dichloromethane andpurified by chromatography on silica using a gradient of 0-100% ethylacetate in cyclohexane gradient over 80 minutes. Fractions were combinedand evaporated in-vacuo to yield the title compound as a colourless oil(768 mg).

LCMS (System B): t_(RET)=1.19 min; MH⁺ 437

Intermediate 7: 2-(Ethoxymethyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one

A stirred mixture of 3-amino-2-ethoxycarbonylpyrrole hydrochloride (2.23g, 11.70 mmol) and 2-ethoxyacetimidamide (2.086 g, 15.21 mmol) ino-xylene (20 mL) was heated to reflux for 23 h. The reaction mixture wasconcentrated in vacuo to remove most of the o-xylene and give a samplewhich contained the title compound (3.8 g).

LCMS (System B): t_(RET)=0.52 min; MH⁺ 194

Intermediate 8: 4-Chloro-2-(ethoxymethyl)-5H-pyrrolo[3,2-d]pyrimidine

Phosphorus oxychloride (21.81 mL, 234 mmol) was added to a crude sampleof 2-(ethoxymethyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (2.26 g). Theresultant mixture was heated at 100° C. for 3 hours. The reactionmixture was cooled to room temperature then poured carefully onto ice.The mixture was treated with aqueous sodium hydroxide solution (5M)until the pH was 7. The resultant mixture was extracted with ethylacetate (2×200 mL). The combined organic extracts were washed withbrine, dried using an hydrophobic frit and concentrated in vacuo toyield 920 mg of orange oil. The crude product was purified by columnchromatography (100 g Si column) using a gradient of 0-100%EtOAc/cyclohexane over 60 minutes. Fractions containing the desiredproduct were combined and concentrated in vacuo to give the titlecompound as a yellow solid (501 mg).

LCMS (System B): t_(RET)=0.67 min; MH⁺ 212, 214

Intermediate 9:4-Chloro-2-(ethoxymethyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidine

Prepared similarly to Intermediate 4 from4-chloro-2-(ethoxymethyl)-5H-pyrrolo[3,2-d]pyrimidine.

LCMS (System B): t_(RET)=0.85 min; MH⁺ 338, 340

Intermediate 10:5-((Benzyloxy)methyl)-4-chloro-2-(ethoxymethyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidine

Prepared similarly to Intermediate 5 from4-chloro-2-(ethoxymethyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidine.

LCMS (System B): t_(RET)=1.27 min; MH⁺ 458, 460

Intermediate 11:5-((Benzyloxy)methyl)-2-(ethoxymethyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amine

5-((Benzyloxy)methyl)-2-butyl-4-chloro-7-iodo-6-methyl-5H-pyryrrolo[3,2-d]pyrimidine(1.2 g, 2.55 mmol) was suspended in isopropanol (4 mL) and 0.88 ammonia(4.24 mL, 77 mmol) was added. The reaction was stirred and heated at120° C. for 2 h in a Biotage Initiator microwave. A further portion of0.88 ammonia (4.24 mL, 77 mmol) was added and the reaction was stirredat 120° C. for 2 h in a Biotage Initiator microwave. A further portionof 0.88 ammonia (4.24 mL, 77 mmol) was added to the reaction and thereaction was stirred at 120° C. for 2 hours in a Biotage Initiatormicrowave. The reaction was evaporated in vacuo and the crude productwas purified by column chromatography (100 g Si column) using a gradient0-50% EtOAc/cyclohexane over 60 minutes. Appropriate fractions werecombined and concentrated in vacuo to give the title compound as a whitesolid (634 mg).

LCMS (System B): t_(RET)=1.24 min; MH⁺ 451

Intermediate 12: Ethyl3-(3-methoxypropanimidamido)-1H-pyrrole-2-carboxylate hydrochloride

Prepared similarly to Intermediate 1 from ethyl3-amino-1H-pyrrole-2-carboxylate hydrochloride and3-methoxypropanenitrile.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.23 (br. s, 1H) 10.99 (br. s, 1H) 9.48(br. s, 1H) 8.35 (br. s, 1H) 7.05-7.13 (m, 1H) 6.15-6.20 (m, 1H) 4.23(q, J=7.0 Hz, 2H) 3.73 (t, J=6.3 Hz, 2H) 3.32 (s, 3H) 2.84 (t, J=6.27Hz, 2H) 1.27 (t, J=7.2 Hz, 3H)

Intermediate 13: 2-(2-Methoxyethyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one

Prepared similarly to Intermediate 2 from ethyl3-(3-methoxypropanimidamido)-1H-pyrrole-2-carboxylate hydrochloride.

LCMS (System B): t_(RET)=0.48 min; MH⁺ 194

Intermediate 14: 4-Chloro-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine

Prepared similarly to Intermediate 3 from2-(2-methoxyethyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5)-one.

LCMS (System B): t_(RET)=0.62 min; MH⁺ 212, 214

Intermediate 15:4-Chloro-7-iodo-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine

N-iodosuccinimide (892 mg, 3.97 mmol) was added portionwise to a stirredsolution of 4-chloro-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine (730mg, 3.45 mmol) in tetrahydrofuran (THF) (30 mL). The resultant mixturewas stirred at room temperature for 1 hour. The reaction mixture wasdiluted with TBME (50 mL) then washed with aqueous sodium thiosulphatesolution (50 mL) then saturated aqueous sodium chloride solution (20mL). The organic phase was dried and filtered using a hydrophobic fritand evaporated to give the title compound (1.17 g).

LCMS (System B): t_(RET)=0.81 min; MH⁺ 338, 340

Intermediate 16:5-((Benzyloxy)methyl)-4-chloro-7-iodo-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine

To a stirred suspension of sodium hydride 60% wt. on mineral oil (0.180g, 4.51 mmol) in anhydrous tetrahydrofuran (8 mL) at 0° C. was added asolution of4-chloro-7-iodo-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine (1.17 g,3.47 mmol) in tetrahydrofuran (8 mL) dropwise over 5 minutes. Theresultant mixture was stirred at 0° C. for 15 minutes before theaddition of a solution of benzylchloromethyl ether (0.504 mL, 3.64 mmol)in tetrahydrofuran (5 mL) dropwise over 5 min. The reaction was stirredfor two hours. The reaction was partitioned between ethyl acetate (200mL) and water (200 mL). The organic layer was separated and washed withbrine (200 mL), dried, filtered and concentrated in vacuo to give thecrude compound (1.57 g). The sample was dissolved in dichloromethane andpurified by chromatography on silica (70 g) using a gradient of 0-50%ethyl acetate-cyclohexane over 60 minutes. The appropriate fractionswere combined and evaporated in vacuo to give the title compound as asolid (985 mg).

LCMS (System B): t_(RET)=1.23 min; MH⁺ 458, 460

Intermediate 17:5-((Benzyloxy)methyl)-7-iodo-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To solid5-((benzyloxy)methyl)-4-chloro-7-iodo-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine(555 mg, 1.213 mmol) was added isopropanol (3 mL) and ammonia 880 (0.75mL, 13.56 mmol). The reaction vessel was sealed and heated in a BiotageInitiator using initial absorption setting very high to 150° C. for 1 h.To the reaction was added further ammonia 880 (0.75 mL, 13.56 mmol) andthe reaction vessel was sealed and heated in a Biotage Initiator usinginitial absorption setting very high to 150° C. for 1 h. Reaction wasconcentrated in vacuo and the mixture was partitioned between ethylacetate (50 mL) and water (50 mL) and separated. The aqueous layer wasback extracted with ethyl acetate (25 mL) and the combined organics werewashed with brine (25 mL), dried using a hydrophobic frit andconcentrated in vacuo to give a brown gum. The sample was dissolved indichloromethane and purified by chromatography on silica (Si) (50 g)using a 0-100% ethyl acetate-dichloromethane gradient over 40 mins. Theappropriate fractions were combined and evaporated in vacuo to give thetitle compound as a yellow gum (349 mg).

(System B): t_(RET)=0.99 min; MH⁺ 439

Intermediate 18: Ethyl5-methyl-3-pentanimidamido-1H-pyrrole-2-carboxylate hydrochloride

Hydrogen chloride in dioxane (4M, 308 mL, 1.2 mol) was added dropwise toethyl 3-amino-5-methyl-1H-pyrrole-2-carboxylate (38.3 g, 228 mmol) (J.Med. Chem. 2008, 51, 68) in valeronitrile (383 mL). The resultantmixture was heated at 50° C. overnight. An additional portion of acid(160 mL, 0.64 mol) was added and the mixture heated at 55° C. overnight.The reaction mixture was cooled to room temperature, filtered and thefiltrate evaporated. The residue was slurried in TBME (1200 ml) for 30minutes then the solid was filtered and washed with TMBE and dried. Thetitle compound was obtained as a brown solid (58.9 g).

¹H NMR (400 MHz, DMSO-d₆) δ ppm includes 11.90 (br. s, 1H) 11.09 (s, 1H)9.52 (br. s, 1H) 8.14 (br. s, 1H) 5.82 (br. s, 1H) 4.12 (q, J=7.1 Hz,2H) 3.48 (br. s., 1H) 2.14 (s, 3H) 1.51-1.70 (m, 2H) 1.05-1.40 (m, 6H)0.84 (t, J=7.1 Hz, 3H)

Intermediate 19: 2-Butyl-6-methyl-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one

Aqueous sodium hydroxide solution (6M, 138 mL) was added dropwise to asolution of ethyl 5-methyl-3-pentanimidamido-1H-pyrrole-2-carboxylate(58.9 g, 0.2 mol) in ethanol (550 mL) cooled in an ice-bath. Thereaction mixture was heated at reflux for 2.5 hours then cooled to roomtemperature. Water (700 mL) was added and the pH adjusted to pH 6.5using aqueous citric acid (2M). The resultant mixture was stirred for 45minutes then filtered and the solid material washed with water. Thematerial was dried in a vacuum oven at 50° C. to give the titlecompound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm includes 11.60 (s, 1H) 11.53 (s, 1H)5.91 (s, 1H) 2.33-2.50 (m, 2H) 2.19 (s, 3H) 1.45-1.60 (m, 2H) 1.10-1.26(m, 2H) 0.70-0.84 (m, 3H)

Intermediate 20: 2-Butyl-4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine

Phosphorus oxychloride (42.8 mL, 70.4 g, 0.459 mol) was added dropwiseto a solution of 2-butyl-6-methyl-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one(37.5 g, 0.183 mol) in acetonitrile (750 mL) under an atmosphere ofnitrogen. The reaction mixture was heated at reflux overnight. Aftercooling to room temperature an additional portion of phosphorusoxychloride (42.8 mL, 70.4 g, 0.459 mol) was added dropwise and heatingcontinued for a further 3.5 hours. The reaction was cooled to roomtemperature again and a further portion of phosphorus oxychloride (42.8mL, 70.4 g, 0.459 mol) was added dropwise and heating continued for 3hours. The reaction mixture was allowed to stand at room temperatureovernight then heated at reflux for 3.5 hours. The reaction mixture wascooled then concentrated. The residue was cooled in an ice-bath andice-cold water (650 mL) was added carefully. The pH was adjusted to 8using aqueous potassium hydroxide solution and then mixture stirred for45 minutes. The mixture was partitioned between dichloromethane (1000mL) and water (1000 mL). The aqueous layer and solid material wasre-extracted with dichloromethane (2×500 mL). The combined organiclayers were dried (Na₂SO₄) and filtered through a plug of neutralalumina. The filtrate was concentrated to a yellow oil, a seed crystaland hexane were added. The solid material was filtered, washed withhexane and dried to give the title compound as an off-white solid (15.5g).

LCMS (System A): t_(RET)=0.81 min; MH⁺ 224/226

Intermediate 21:2-Butyl-4-chloro-7-iodo-6-methyl-5H-pyrrolo[3,2-d]pyrimidine

Prepared similarly to Intermediate 4 from2-butyl-4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine.

LCMS (System B): t_(RET)=1.20 min; MH⁺ 350, 352

Intermediate 22:5-((Benzyloxy)methyl)-2-butyl-4-chloro-7-iodo-6-methyl-5H-pyrrolo[3,2-d]pyrimidine

Prepared similarly to Intermediate 5 from2-butyl-4-chloro-7-iodo-6-methyl-5H-pyrrolo[3,2-d]pyrimidine.

LCMS (System B): t_(RET)=1.54 min; MH⁺ 470, 472

Intermediate 23:5-((Benzyloxy)methyl)-2-butyl-7-iodo-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 6 from5-((benzyloxy)methyl)-2-butyl-4-chloro-7-iodo-6-methyl-5H-pyrrolo[3,2-d]pyrimidine.

LCMS (System B): t_(RET)=1.24 min; MH⁺ 451

Intermediate 24:2-Butyl-4-chloro-7-iodo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidine

To a stirred suspension of sodium hydride 60% wt. on mineral oil (0.248g, 6.20 mmol) in anhydrous THF (20 mL) at 0° C. was added a solution of2-butyl-4-chloro-7-iodo-5H-pyrrolo[3,2-d]pyrimidine (1.3 g, 3.87 mmol)in THF (20 mL) dropwise over 5 min. The resultant mixture was stirred at0° C. for 15 minutes before the addition of a solution of(2-(chloromethoxy)ethyl)trimethylsilane (0.720 mL, 4.07 mmol) in THF (10mL) dropwise over 5 min. The reaction was stirred for two hours thenquenched with water. The reaction was partitioned between ethyl acetate(100 mL) and water (100 mL). The organic was separated and washed withbrine (100 mL), dried, filtered and concentrated in vacuo to give thetitle compound (1.86 g) as a red oil.

LCMS (System B): t_(RET)=1.65 min; MH⁺ 466

Intermediate 25:2-Butyl-7-iodo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 17 from2-butyl-4-chloro-7-iodo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidine.

LCMS (System B): t_(RET)=1.38 min; MH⁺ 447

Intermediate 26: 1-(Hex-5-yn-1-yl)piperidine

A solution of 6-chlorohex-1-yne (5 mL, 41.3 mmol), piperidine (4.08 mL,41.3 mmol) and sodium hydrogen carbonate (4.16 g, 49.5 mmol) in DMF (50mL) was refluxed for 16 hr. The reaction was concentrated in vacuo andthe residue partitioned between ether (150 mL) and water (150 mL). Theorganic was separated and the aqueous back extracted with diethyl ether(50 mL). The combined organics were washed with brine (150 mL), dried(MgSO₄), filtered and concentrated in vacuo to give a crude sample ofthe title compound (3.74 g). Oxalic acid (2.161 g, 24 mmol) was added tothe crude product. The resultant solid was recrystallised from ethanol,collected by filtration and dried in vacuo to give1-(hex-5-yn-1-yl)piperidine oxalic acid salt (4.66 g). The solid waspartitioned between diethyl ether (150 mL) and saturated aqueous sodiumbicarbonate (150 mL). The organic was separated and dried (MgSO₄)filtered and concentrated in vacuo to give the title compound as ayellow oil (1.93 g).

¹H NMR (400 MHz, CDCl₃) δ ppm 2.31-2.52 (m, 6H) 2.18-2.26 (m, 2H)1.92-1.96 (m, 1H) 1.40-1.72 (m, 10H)

Intermediate 27: 1-(Pent-4-yn-1-yl)piperidine

A mixture of piperidine (11.6 mL, 117 mmol), 5-chloro-1-pentyne (13.8mL, 129 mmol) and sodium hydrogen carbonate (11.84 g, 141 mmol) in DMF(100 mL) under argon was heated at 80° C. for 18 hours. The reactionmixture was diluted with ice cold water then extracted with ethylacetate. The phases were separated and the organic phase washed withwater (100 mL), saturated brine (25 mL), dried over sodium sulphate andevaporated in vacuo to give the crude product as an orange liquid. Thecrude product was purified by chromatography on silica eluting with 10%methanol in DCM. The title compound was obtained as a red liquid (5.05g).

¹H NMR (400 MHz, CDCl₃) δ ppm 2.30-2.50 (m, 6H) 2.15-2.30 (m, 2H)1.90-1.99 (m, 1H), 1.65-1.78 (m, 2H), 1.50-1.63 (m, 4H) 1.33-1.48 (m,2H)

Intermediate 28:5-((Benzyloxy)methyl)-2-butyl-7-(6-(piperidin-1-yl)hex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a degassed solution of5-((benzyloxy)methyl)-2-butyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amine(217 mg, 0.497 mmol) in anhydrous N,N-dimethylformamide (3.5 mL) under anitrogen atmosphere at room temperature was added copper(I) iodide (19mg, 0.1 mmol), bis(triphenylphosphine)palladium(II)dichloride (38.4 mg,0.055 mmol) and finally triethylamine (0.124 mL, 0.895 mmol). Themixture was stirred at room temperature under a nitrogen atmosphere for10 minutes and then a solution of 1-(hex-5-yn-1-yl)piperidine (132 mg,0.796 mmol) in anhydrous degassed N,N-dimethylformamide (0.5 mL) wasadded. The reaction mixture was stirred at 55° C. for 40 minutes. Thereaction was evaporated in vacuo to yield a dark red oil. The oil waspartitioned between water and dichloromethane. The organic layer wasseparated and the aqueous back extracted with dichloromethane. Thecombined organic extracts were passed through a hydrophobic frit andevaporated in vacuo to yield a dark red oil. The oil was dissolved inMeOH:DMSO (1:1) (5×1 mL) purified by MDAP (Method B). Appropriatefractions were combined and evaporated in vacuo to yield the titlecompound as a yellow oil (161 mg).

LCMS (System B): t_(RET)=1.26 min; MH⁺ 474

Intermediate 29:2-Butyl-7-(6-(piperidin-1-yl)hex-1-yn-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a degassed stirred solution of2-butyl-7-iodo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(400 mg, 0.896 mmol), copper (I) iodide (34 mg, 0.179 mmol) andbis(triphenylphosphine)palladium(II)dichloride (63 mg, 0.090 mmol) inanhydrous N,N-dimethylformamide (6 mL) was added a solution of1-(hex-5-yn-1-yl)piperidine (193 mg, 1.165 mmol) and triethylamine(0.186 mL, 1.344 mmol) in anhydrous N,N-dimethylformamide (3 mL)dropwise over 5 minutes. The reaction was stirred at ambient temperatureunder a nitrogen atmosphere for 20 hours. The reaction was concentratedin vacuo and the residue partitioned between ethyl acetate (50 mL) andwater (50 mL). The organic phase was separated and the aqueous backextracted with ethyl acetate (50 mL). The combined organics were washedwith brine (50 mL), dried (MgSO₄), filtered and concentrated in vacuo togive an orange gum. The sample was dissolved in dichloromethane andpurified on a silica (Si) cartridge (50 g) using a 0-10%methanol-dichloromethane gradient over 40 minutes. The appropriatefractions were combined and evaporated in vacuo to give the titlecompound as a yellow foam (87 mg).

LCMS (System A): t_(RET)=0.71 min; MH⁺ 484

Intermediate 30:2-Butyl-7-(6-(piperidin-1-yl)hexyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

A solution of2-butyl-7-(6-(piperidin-1-yl)hex-1-yn-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(87 mg, 0.180 mmol) in ethanol (8 mL) and acetic acid (1 mL) washydrogenated using the H-cube (settings: 60° C., Full H₂, 1 mL/min flowrate) and 10% Pd/C CatCart 30 as the catalyst. The reaction wasconcentrated in vacuo and the residue partitioned between DCM (20 mL)and 2N aqueous sodium hydroxide (20 mL). The organic layer was separatedand dried using a hydrophobic frit before concentration in vacuo to givethe title compound (50 mg).

LCMS (System A): t_(RET)=0.86 min; MH⁺ 488

Intermediate 31:5-((Benzyloxy)methyl)-2-butyl-7-(5-(piperidin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a degassed solution of5-((benzyloxy)methyl)-2-butyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amine(175 mg, 0.401 mmol) in anhydrous N,N-dimethylformamide (3 mL) undernitrogen atmosphere at room temperature was added copper(I) iodide (15mg, 0.079 mmol), bis(triphenylphosphine)palladium(II)dichloride (31 mg,0.044 mmol) and finally triethylamine (0.1 mL, 0.722 mmol). The mixturewas stirred at room temperature under nitrogen atmosphere for 10 minutesand then a solution of 1-(pent-4-yn-1-yl)piperidine (97 mg, 0.642 mmol)in anhydrous degassed N,N-dimethylformamide (0.5 mL) was added. Thereaction mixture was stirred at 55° C. for 40 minutes. The reaction wasevaporated in vacuo to yield a dark yellow oil. The oil was partitionedbetween water and dichloromethane. The organic layer was separated andthe aqueous back extracted with dichloromethane. The combined organicextracts were passed through a hydrophobic frit and evaporated in vacuoto yield a dark yellow oil. The oil was dissolved in MeOH:DMSO (1:1)(4×1 mL) and purified by MDAP (Method B). Appropriate fractions werecombined and evaporated in vacuo to yield the title compound as a paleyellow solid (73 mg).

LCMS (System B): t_(RET)=1.26 min; MH⁺ 460

Intermediate 32:5-((Benzyloxy)methyl)-2-butyl-7-(4-(piperidin-1-yl)but-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 26 from5-((benzyloxy)methyl)-2-butyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amineand 1-(but-3-yn-1-yl)piperidine (Eur J. Med. Chem. 2009, 44(10), 4098).

LCMS (System B): t_(RET)=1.11 min; MH⁺ 446

Intermediate 33:5-((Benzyloxy)methyl)-2-(ethoxymethyl)-7-(6-(piperidin-1-yl)hex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 26 from5-((benzyloxy)methyl)-4-chloro-7-iodo-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidineand 1-(hex-5-yn-1-yl)piperidine.

LCMS (System B): t_(RET)=1.16 min; MH⁺ 476

Intermediate 34:5-((Benzyloxy)methyl)-2-(2-methoxyethyl)-7-(6-(piperidin-1-yl)hex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a degassed solution of5-((benzyloxy)methyl)-7-iodo-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(264 mg, 0.602 mmol) in anhydrous N,N-dimethylformamide (7 mL) undernitrogen atmosphere at room temperature was added copper (I) iodide(22.94 mg, 0.120 mmol), bis(triphenylphosphine)palladium(II)dichloride(42.3 mg, 0.060 mmol) and finally triethylamine (0.125 mL, 0.904 mmol).The mixture was stirred at room temperature under a nitrogen atmospherefor 10 minutes and then a solution of 1-(hex-5-yn-1-yl)piperidine (129mg, 0.783 mmol) in anhydrous degassed N,N-dimethylformamide (1 mL) wasadded. The reaction mixture was stirred at room temperature for 16hours. 1-(Hex-5-yn-1-yl)piperidine (129 mg, 0.783 mmol) was added andthe mixture was stirred at room temperature for 1 hour. The reaction wasevaporated in vacuo to yield a brown oil. The oil was partitionedbetween water (25 mL) and dichloromethane (25 mL). The organic layer wasseparated and the aqueous back extracted with dichloromethane (20 mL).The combined organic extracts were passed through a hydrophobic frit andevaporated in vacuo to yield an orange oil. The sample was dissolved indichloromethane and purified by chromatography on silica (50 g) using agradient of 0-100% ethyl acetate in cyclohexane over 60 minutes. Theappropriate fractions were combined and evaporated in vacuo to give thetitle compound as an oil (102 mg).

LCMS (System B): t_(RET)=1.08 min; MH⁺ 476

Intermediate 35:5-((Benzyloxy)methyl)-2-butyl-6-methyl-7-(6-(piperidin-1-yl)hex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a degassed solution of5-((benzyloxy)methyl)-2-butyl-7-iodo-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine(215 mg, 0.477 mmol) in anhydrous N,N-dimethylformamide (4 mL) under anitrogen atmosphere at room temperature was added copper (I) iodide (19mg, 0.100 mmol), bis(triphenylphosphine)palladium(II)dichloride (36.9mg, 0.053 mmol) and finally triethylamine (0.119 mL, 0.859 mmol). Themixture was stirred at room temperature under a nitrogen atmosphere for10 minutes and then a solution of 1-(hex-5-yn-1-yl)piperidine (126 mg,0.764 mmol) in anhydrous degassed N,N-dimethylformamide (2 mL) wasadded. The reaction mixture was stirred at 55° C. for 1.5 hours. Copper(I) iodide (19 mg, 0.100 mmol),bis(triphenylphosphine)palladium(II)dichloride (36.9 mg, 0.053 mmol) and1-(hex-5-yn-1-yl)piperidine (126 mg, 0.764 mmol) were added and thereaction mixture was left to stir at 55° C. for 1 hour. The reaction wasevaporated in vacuo to yield a dark red oil. The oil was partitionedbetween water and dichloromethane. The organic layer was separated andthe aqueous back extracted with dichloromethane. The combined organicextracts were passed through a hydrophobic frit and evaporated in vacuoto yield a dark red oil. The crude product was purified by MDAP (MethodB). Fractions which contained product were concentrated to give thetitle compound as a yellow oil (134 mg).

LCMS (System B): t_(RET)=1.33 min; MH⁺ 488

Intermediate 36:5-((Benzyloxy)methyl)-2-butyl-6-methyl-7-(4-(piperidin-1-yl)but-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 28 from5-((benzyloxy)methyl)-2-butyl-7-iodo-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amineand 1-(but-3-yn-1-yl)piperidine.

LCMS (System B): t_(RET)=1.29 min; MH⁺ 460

Intermediate 37:5-((Benzyloxy)methyl)-2-butyl-7-(5-chloropent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a degassed suspension of5-((benzyloxy)methyl)-2-butyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amine(2.768 g, 6.34 mmol), copper (I) iodide (0.242 g, 1.269 mmol), andbis(triphenylphosphine)palladium(II)dichloride (0.445 g, 0.634 mmol) inanhydrous N,N-dimethylformamide (40 mL) was added a solution of5-chloropent-1-yne (0.781 g, 7.61 mmol) and triethylamine (1.231 mL,8.88 mmol) in anhydrous N,N-dimethylformamide (20 mL) dropwise over 2minutes. The reaction was stirred at ambient temperature for 17 hours.The reaction was concentrated in vacuo and the resultant brown oilpartitioned between water (500 mL) and ethyl acetate (500 mL). Theorganic phase was separated and the aqueous back extracted with ethylacetate (250 mL). The combined organics were washed with brine (400 mL),dried (MgSO₄), filtered and concentrated in vacuo. The sample wasdissolved in dichloromethane and purified by chromatography on silica(Si) (2×100 g) using a 0-100% ethyl acetate-cyclohexane gradient over 60minutes. The appropriate fractions were combined and evaporated in vacuoto give a red oil. The sample was dissolved in dichloromethane andpurified by chromatography on silica using a 0-100% ethylacetate-cyclohexane gradient over 80 minutes. The appropriate fractionswere combined and evaporated in vacuo to give the title compound as ayellow solid. (1.13 g)

LCMS (System B): t_(RET)=1.29 min; MH⁺ 411, 413

Intermediate 38:5-((Benzyloxy)methyl)-2-butyl-7-(5-(pyrrolidin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a stirred solution of5-((benzyloxy)methyl)-2-butyl-7-(5-chloropent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(150 mg, 0.365 mmol) and triethylamine (0.061 mL, 0.438 mmol) inanhydrous acetonitrile (3 mL) at ambient temperature was addedpyrrolidine (0.033 mL, 0.402 mmol) in one charge. The reaction wasstirred at ambient temperature for 1.5 hours then at 60° C. for 2.5hours. Heating at 80° C. was continued for 16 h. Further pyrrolidine(0.033 mL, 0.402 mmol) and triethylamine (0.061 mL, 0.438 mmol) wereadded and heating at 80° C. continued for 10 hours. The reaction wasconcentrated in vacuo and the residue partitioned betweendichloromethane (10 mL) and water (10 mL). The organic phase wasseparated and dried (hydrophobic frit) before concentration in vacuo.The sample was dissolved in dichloromethane and purified bychromatography on an aminopropyl (NH₂) silica using a 0-100% ethylacetate-dichloromethane gradient over 20 minutes. The appropriatefractions were combined and evaporated in vacuo to give the titlecompound as an off-white solid (95 mg).

LCMS (System B): t_(RET)=1.23 min; MH⁺ 446

Intermediate 39:6-(4-Amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)hex-5-yn-1-ol

To solid5-((benzyloxy)methyl)-2-butyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amine(1.2 g, 2.75 mmol) in N,N-dimethylformamide (20 mL) was addedbis(triphenylphosphine)palladium(II)dichloride (0.193 g, 0.275 mmol) andcopper(I) iodide (0.105 g, 0.550 mmol). The solution was stirred anddegassed with nitrogen for 5 minutes then the reaction mixture placedunder a nitrogen atmosphere. A solution of hex-5-yn-1-ol (0.405 g, 4.13mmol) and triethylamine (0.575 mL, 4.13 mmol) in N,N-dimethylformamide(5 mL) was added dropwise over 5 minutes. The reaction mixture wasstirred at ambient temperature for 24 h. Additional hex-5-yn-1-ol (0.1g, 1.02 mmol) and triethylamine (0.15 mL, 1.08 mmol) inN,N-dimethylformamide (3 mL) was added dropwise over 5 minutes and thereaction mixture stirred at ambient temperature for a further 5 hours.The reaction mixture was concentrated in vacuo at 60° C. and the residuepartitioned between ethyl acetate (100 mL) and water (100 mL). Theorganic layer was separated and the aqueous layer back extracted withethyl acetate (3×50 mL). The combined organic phases were washed withbrine, dried (hydrophobic frit) and concentrated in vacuo to a viscousbrown oil (2.00 g). The sample was dissolved in dichloromethane andpurified by chromatography on aminopropyl silica (110 g) using agradient of 0-100% ethyl acetate-cyclohexane followed by a gradient of0-20% methanol-ethyl acetate over 40 minutes. The appropriate fractionswere combined, evaporated in vacuo, then azeotroped with diethyl etherand dried to give a sticky off-white solid (699 mg). The sample wasloaded in dichloromethane and re-purified by chromatography on silica(Si) (50 g) using a 0-100% ethyl acetate-dichloromethane gradient over40 mins. The appropriate fractions were combined and evaporated in vacuoto give the title compound as a white solid (505 mg).

LCMS (System B): t_(RET)=1.04 min; MH⁺ 407

Intermediate 40:6-(4-Amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)hex-5-ynal

A mixture of6-(4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)hex-5-yn-1-ol(505 mg, 1.242 mmol), N-methylmorpholine N-oxide (218 mg, 1.863 mmol),powdered 4 Å molecular sieves and tetrapropylammonium perruthenate(21.83 mg, 0.062 mmol) was placed under nitrogen and anhydrousdichloromethane (18 mL) and anhydrous acetonitrile (2 mL) added. Thereaction mixture was stirred at ambient temperature for 2 hours. Thereaction mixture was concentrated in vacuo at 60° C. The residue wasdissolved in dichloromethane, filtered through a pad of celite andconcentrated in vacuo to give a as a black gum (678 mg). The sample wasdissolved in dichloromethane and purified by chromatography on a silicacartridge (50 g) using a 0-10% methanol-dichloromethane gradient over 40mins. The appropriate fractions were combined and evaporated in vacuo togive a yellow gum with black discolouration (399 mg). The sample wasdissolved in dichloromethane and re-purified on silica (50 g) using a0-10% methanol-dichloromethane gradient over 40 minutes. The appropriatefractions were combined and evaporated in vacuo to give the titlecompound as a yellow gum (227 mg).

LCMS (System B): t_(RET)=1.11 min; MH⁺ 405

Intermediate 41:5-((Benzyloxy)methyl)-2-butyl-7-(6-(pyrrolidin-1-yl)hex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

A suspension of6-(4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)hex-5-ynal(117 mg, 0.289 mmol) and 4 Å molecular sieves in anhydrousdichloromethane (7 mL) was placed under nitrogen and pyrrolidine (0.048mL, 0.578 mmol) added. The reaction mixture was stirred at ambienttemperature for 1 minute then sodium triacetoxyborohydride (61.3 mg,0.289 mmol) added and the reaction stirred for a further 1 hour.Additional pyrrolidine (0.025 mL, 0.301 mmol) and sodiumtriacetoxyborohydride (80 mg, 0.377 mmol) were added and the reactionmixture stirred for a further 30 minutes The reaction mixture wasfiltered through celite and the cake washed with DCM. The solvent wasremoved in vacuo and the residue redissolved in DCM (20 mL). The organiclayer was washed with saturated sodium hydrogen carbonate solution (20mL), the layers separated and the aqueous layer back-extracted with DCM(20 mL). The combined organic phases were dried through a hydrophobicfrit and concentrated in vacuo to give a yellow gum. The sample wasdissolved in dichloromethane and purified on aminopropyl silica (10 g)using a 0-100% ethyl acetate-cyclohexane followed 0-20% methanolgradient over 40 minutes. The appropriate fractions were combined andevaporated in vacuo to give the title compound as a white solid (55 mg).

LCMS (System B): t_(RET)=1.17 min; MH⁺ 460

Intermediate 42: 2-Pentyl-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one

A suspension of ethyl 3-amino-1H-pyrrole-2-carboxylate, hydrochloride (3g, 15.74 mmol), hexanenitrile (30 g, 309 mmol) and 4M hydrochloric acidin dioxane (20 mL, 80 mmol) was stirred at 50° C. for 20 hours. Thereaction mixture was allowed to cool to ambient temperature, uponcooling a precipitate formed. To the reaction was added further 4Mhydrochloric acid in dioxane (10 mL) and the reaction mixture was heatedat 50° C. for a further 4 hours. The reaction mixture was allowed tocool to ambient temperature then diluted with TBME (300 mL) and theresultant suspension filtered. The solid cake was washed with TBME (150mL) and diethyl ether (150 mL) and dried in vacuo to give a biege solid(4.4 g). The solid was dissolved in ethanol (45 mL) and treated with asolution of sodium hydroxide (2.52 g, 62.9 mmol) in water (10 mL) thenthe mixture was heated to 80° C. for 4 hours. The reaction solvent wasremoved in vacuo. The residue was suspended in water (200 mL) and the pHadjusted to 4 with solid citric acid, and extracted with ethyl acetate(2×200 mL). The combined organic extracts were dried (MgSO₄), filteredand concentrated in vacuo to give a sticky biege solid. The solid wastriturated with diethyl ether and the resultant suspension filtered anddried in vacuo to give the title compound as an off white solid (1.884g).

LCMS (System B): t_(RET)=0.72 min; MH⁺ 206

Intermediate 43: 4-Chloro-2-pentyl-5H-pyrrolo[3,2-d]pyrimidine

A stirred suspension of 2-pentyl-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one(1.88 g, 9.16 mmol) in phosphorus(V) oxychloride (20 mL, 215 mmol) washeated to 100° C. for 3 hours. The reaction mixture was concentrated invacuo and azeotroped with toluene. The resultant gum was dissolved inDCM (100 mL) and washed with water (100 mL) and was dried (hydrophobicfrit) before being concentrated in vacuo to give a brown solid. Thesample was dissolved in dichloromethane and purified by chromatographyon a silica cartridge (50 g) using a 0-25% MeOH:TBME gradient over 40minutes. The appropriate fractions were combined and evaporated in vacuoto give a brown solid, this was triturated with diethyl ether (ca. 100mL), the resultant suspension was filtered and the solid dried in vacuoto give the title compound as a pale brown solid (1.04 g).

LCMS (System B): t_(RET)=0.99 min; MH⁺ 224, 226

Intermediate 44: 4-Chloro-7-iodo-2-pentyl-5H-pyrrolo[3,2-d]pyrimidine

Prepared similarly to Intermediate 15 from4-chloro-2-pentyl-5H-pyrrolo[3,2-d]pyrimidine

LCMS (System B): t_(RET)=1.21 min; MH⁺ 350, 352

Intermediate 45:5-((Benzyloxy)methyl)-4-chloro-7-iodo-2-pentyl-5H-pyrrolo[3,2-d]pyrimidine

To a stirred slurry of sodium hydride 60% wt. on mineral oil (0.167 g,4.17 mmol) in anhydrous THF (15 mL) at 0° C. under a nitrogen atmospherewas added a solution of4-chloro-7-iodo-2-pentyl-5H-pyrrolo[3,2-d]pyrimidine (1.268 g, 3.63mmol) in anhydrous THF (10 mL) dropwise over 10 minutes. The reactionwas stirred at 0° C. for a further 30 minutes before addition of asolution of ((chloromethoxy)methyl)benzene (0.653 g, 4.17 mmol) inanhydrous THF (10 mL) dropwise over 10 minutes. The reaction was thenallowed to warm to ambient temperature and stirred for a further 60minutes. To the reaction was added further sodium hydride 60% wt. onmineral oil (30 mg, 0.75 mmol) and stirring at ambient temperature wascontinued for 16 hours. The reaction was partitioned between water (120mL) and ethyl acetate (120 mL). The organic phase was separated and theaqueous layer back extracted with ethyl acetate (50 mL). The combineorganic extracts were washed with brine (100 mL), dried (MgSO₄),filtered and concentrated in vacuo to give an orange oil. The sample wasdissolved in dichloromethane and purified by chromatography on a silicacartridge (100 g) using a 0-50% ethyl acetate-cyclohexane gradient over60 mins. The appropriate fractions were combined and evaporated in vacuoto give the title compound as a yellow oil (1.478 g).

LCMS (System B): t_(RET)=1.51 min; MH⁺ 470, 472

Intermediate 46:5-((Benzyloxy)methyl)-7-iodo-2-pentyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 17 from5-((benzyloxy)methyl)-4-chloro-7-iodo-2-pentyl-5H-pyrrolo[3,2-d]pyrimidine

LCMS (System B): t_(RET)=1.26 min; MH⁺ 451

Intermediate 47:5-((Benzyloxy)methyl)-2-pentyl-7-(6-(piperidin-1-yl)hex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 29 from5-((benzyloxy)methyl)-7-iodo-2-pentyl-5H-pyrrolo[3,2-d]pyrimidin-4-amineand 1-(hex-5-yn-1-yl)piperidine LCMS (System B): t_(RET)=1.30 min; MH⁺488

Intermediate 48:7-(5-(Azepan-1-yl)pent-1-yn-1-yl)-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 38 from5-((benzyloxy)methyl)-2-butyl-7-(5-chloropent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amineand azepane.

LCMS (System B): t_(RET)=1.27 min; MH⁺ 474

Intermediate 49:4-(4-Amino-5-((benzyloxy)methyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)but-3-yn-1-ol

Prepared similarly to Intermediate 39 from5-((benzyloxy)methyl)-2-(ethoxymethyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amineand but-3-yn-1-ol.

LCMS (System B): t_(RET)=1.07 min; MH⁺ 393

Intermediate 50:4-(4-Amino-5-((benzyloxy)methyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)butan-1-ol

A filtered solution of4-(4-amino-5-((benzyloxy)methyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)but-3-yn-1-ol(853 mg, 2.173 mmol) in ethanol (80 mL) was hydrogenated using theH-cube (settings: 20° C., Full H₂, 1 mL/min flow rate) and a 10% Pd/CCatCart 30 as the catalyst. The solution was re-hydrogenated using theH-cube (settings: 20° C., Full H₂, 1 mL/min flow rate) and a new 10%Pd/C CatCart 30 as the catalyst. The reaction mixture was concentratedin vacuo and the residue was dissolved in dichloromethane and purifiedby chromatography on a silica cartridge (100 g) using a 0-25%methanol-dichloromethane gradient over 60 minutes. The appropriatefractions were combined and evaporated in vacuo to give the titlecompound as a off-white solid (543 mg).

LCMS (System B): t_(RET)=0.83 min; MH⁺ 397

Intermediate 51:4-(4-Amino-5-((benzyloxy)methyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)butanal

To a stirred suspension of4-(4-amino-5-((benzyloxy)methyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)butan-1-ol(230 mg, 0.580 mmol), 4-methymorpholine N-oxide (82 mg, 0.696 mmol) andpowdered 4 Å molecular sieves in a mixture of anhydrous dichloromethane(10 mL) and anhydrous acetonitrile (1 mL) at ambient temperature wasadded tetrapropylammonium perruthenate (22 mg, 0.063 mmol), and thereaction was stirred at ambient temperature for 2 h. The reactionmixture was concentrated in vacuo (water bath 20° C.). The resultantresidue was slurried with DCM (10 mL) and filtered through a pad ofcelite. The resultant solution was concentrated in vacuo andre-dissolved in dichloromethane and purified by chromatography on asilica cartridge (20 g) using a 0-10% methanol-dichloromethane gradientover 40 mins. The appropriate fractions were combined and evaporated invacuo to give the title compound as a yellow gum (114 mg).

LCMS (System B): t_(RET)=1.13 min; MH⁺ 395

Intermediate 52:7-(4-(Azepan-1-yl)butyl)-5-((benzyloxy)methyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

A suspension of4-(4-amino-5-((benzyloxy)methyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)butanal(68 mg, 0.172 mmol) and 4 Å molecular sieves in anhydrousdichloromethane (5 mL) was placed under nitrogen and azepane (0.039 mL,0.345 mmol) added. The reaction mixture was stirred at ambienttemperature for 1 minute then sodium triacetoxyborohydride (73.1 mg,0.345 mmol) added and the reaction stirred for a further 1 hour. Thereaction mixture was filtered through celite and the cake washed withDCM then Methanol. The solvent was removed in vacuo and the residueredissolved in DCM (50 mL). The organic layer was washed with saturatedsodium hydrogen carbonate solution (50 mL), the layers separated and theaqueous layer back-extracted with DCM (25 mL) then 3:1 CHCl₃:IPA (40mL). The combined organics were dried with MgSO₄, filtered andconcentrated in vacuo to give an off-white gum (180 mg). The sample wasloaded in dichloromethane and purified by chromatography on aminopropylcartridge (11 g) using a 0-25% methanol-dichloromethane gradient over 30minutes. The appropriate fractions were combined and evaporated in vacuoto give the title compound as a white solid (42 mg).

LCMS (System B): t_(RET)=1.36 min; MH⁺ 478

Intermediate 53:5-((Benzyloxy)methyl)-2-butyl-7-(6-chlorohex-1-yn-1-yl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 28 from5-((benzyloxy)methyl)-2-butyl-7-iodo-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amineand 6-chlorohex-1-yne.

LCMS (System B): t_(RET)=1.33 min; MH⁺ 439, 441

Intermediate 54:5-((Benzyloxy)methyl)-2-butyl-6-methyl-7-(6-(pyrrolidin-1-yl)hex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a stirred solution of5-((benzyloxy)methyl)-2-butyl-7-(6-chlorohex-1-yn-1-yl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine(160 mg, 0.364 mmol) and triethylamine (0.152 mL, 1.093 mmol) inacetonitrile (4 mL) was added pyrrolidine (0.090 mL, 1.093 mmol). Thereaction was stirred at 80° C. for 18 hours. Additional pyrrolidine(0.045 mL, 0.547 mmol) and triethylamine (0.075 mL, 0.539 mmol) wereadded to the reaction mixture which was stirred at 80° C. for a further2 hours. The reaction mixture was concentrated in vacuo at 60° C. andthe residue paritioned between DCM (25 mL) and water (25 mL). Theorganic layer was separated and the aqueous layer back-extracted withDCM (2×25 mL). The combined organic phases were dried through ahydrophobic frit and concentrated in vacuo to give an orange-brown solid(184 mg). The sample was loaded in dichloromethane and purified bychromatography on an aminopropyl cartridge (NH₂) (10 g) using a 0-50%ethyl acetate-dichloromethane gradient over 40 minutes. The appropriatefractions were combined and evaporated in vacuo to the title compound asa pale yellow gum (157 mg).

LCMS (System B): t_(RET)=1.18 min; MH⁺ 474

Intermediate 55:6-(4-Amino-5-((benzyloxy)methyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)hex-5-yn-1-ol

To solid5-((benzyloxy)methyl)-2-butyl-7-iodo-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine(500 mg, 1.110 mmol) in N,N-dimethylformamide (8 mL) was addedbis(triphenylphosphine)palladium(II)dichloride (78 mg, 0.111 mmol) andcopper(I) iodide (42.3 mg, 0.222 mmol). The solution was stirred anddegassed with nitrogen for 5 minutes then the reaction mixture placedunder a nitrogen atmosphere. A solution of hex-5-yn-1-ol (163 mg, 1.665mmol) and triethylamine (0.232 mL, 1.665 mmol) in N,N-dimethylformamide(2 mL) was added dropwise over 5 minutes. The reaction mixture wasstirred at 50° C. for 6 hours. Additionalbis(triphenylphosphine)palladium(II)dichloride (40 mg, 0.0569 mmol) andcopper(I) iodide (20 mg, 0.105 mmol) was added to the reaction mixturewhich was degassed with nitrogen for 5 mins then placed under a nitrogenatmosphere. A solution of hex-5-yn-1-ol (80 mg, 0.817 mmol) andtriethylamine (0.100 mL, 0.711 mmol) in N,N-dimethylformamide (2 mL) wasadded dropwise over 5 minutes. The reaction mixture was stirred at 50°C. for a further 2.5 hours then allowed to cool to ambient temperatureand stirred for 20 hours (for convenience) and heated to 50° C. for afinal 2 hours. The reaction mixture was concentrated in vacuo at 60° C.and the residue separated between ethyl acetate (100 mL) and water (100mL). The organic layer was separated and the aqueous layer backextracted with ethyl acetate (2×50 mL) and 3:1 CHCl₃:IPA (40 mL). Thecombined organics were dried through a hydrophobic frit and concentratedin vacuo to give a viscous brown oil (1.06 g). The sample was loaded indichloromethane and purified by chromatography on an aminopropylcartridge (NH₂) (70 g) using a 0-100% ethyl acetate-dichloromethanegradient over 60 minutes. The appropriate fractions were combined,evaporated in vacuo and azeotroped with diethyl ether to give the titlecompound as an off-white solid (195 mg).

LCMS (System B): t_(RET)=1.07 min; MH⁺ 421.

Intermediate 56:6-(4-Amino-5-((benzyloxy)methyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)hex-5-ynal

Prepared similarly to Intermediate 40 from6-(4-amino-5-((benzyloxy)methyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)hex-5-yn-1-ol

LCMS (System B): t_(RET)=1.16 min; MH⁺ 419

Intermediate 57:7-(6-(Azetidin-1-yl)hex-1-yn-1-yl)-5-((benzyloxy)methyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 41 from6-(4-amino-5-((benzyloxy)methyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)hex-5-ynaland azetidine.

LCMS (System B): t_(RET)=1.17 min; MH⁺ 460

Intermediate 58:5-((Benzyloxy)methyl)-2-butyl-7-(5-chloropent-1-yn-1-yl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 285-((benzyloxy)methyl)-2-butyl-7-iodo-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amineand 6-chloropent-1-yne.

LCMS (System B): t_(RET)=1.29 min; MH⁺ 425, 427

Intermediate 59:5-((Benzyloxy)methyl)-2-butyl-6-methyl-7-(5-(pyrrolidin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 54 from5-((benzyloxy)methyl)-2-butyl-7-(5-chloropent-1-yn-1-yl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amineand pyrrolidine.

LCMS (System B): t_(RET)=1.17 min; MH⁺ 460

Intermediate 60:5-(4-Amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pent-4-yn-1-ol

Prepared similarly to Intermediate 39 from5-((benzyloxy)methyl)-2-butyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amineand pent-4-yn-1-ol.

LCMS (System B): t_(RET)=1.05 min; MH⁺ 393

Intermediate 61:5-(4-Amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pent-4-ynal

Prepared similarly to Intermediate 40 from5-(4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pent-4-yn-1-ol.

LCMS (System B): t_(RET)=1.08 min; MH⁺ 391

Intermediate 62:7-(5-(Azetidin-1-yl)pent-1-yn-1-yl)-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 41 from5-(4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pent-4-ynaland azetidine.

LCMS (System B): t_(RET)=1.17 min; MH⁺ 432

Intermediate 63:5-(4-Amino-5-((benzyloxy)methyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pent-4-yn-1-ol

Prepared similarly to Intermediate 55 from5-((benzyloxy)methyl)-2-butyl-7-iodo-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amineand pent-4-yn-1-ol.

LCMS (System B): t_(RET)=1.03 min; MH⁺ 407

Intermediate 64:5-(4-Amino-5-((benzyloxy)methyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pent-4-ynal

Prepared similarly to Intermediate 40 from5-(4-amino-5-((benzyloxy)methyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pent-4-yn-1-ol.

LCMS (System B): t_(RET)=1.09 min; MH⁺ 405

Intermediate 65:7-(5-(Azetidin-1-yl)pent-1-yn-1-yl)-5-((benzyloxy)methyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 41 from5-(4-amino-5-((benzyloxy)methyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pent-4-ynaland azetidine.

LCMS (System B): t_(RET)=1.14 min; MH⁺ 446

Intermediate 66:5-((Benzyloxy)methyl)-2-butyl-6-methyl-7-(4-(pyrrolidin-1-yl)butyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 52 from4-(4-amino-5-((benzyloxy)methyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)butanaland pyrrolidine.

LCMS (System B): t_(RET)=1.19 min; MH⁺ 450

Intermediate 67:5-((Benzyloxy)methyl)-2-butyl-7-(5-(4,4-difluoropiperidin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a stirred suspension of5-((benzyloxy)methyl)-2-butyl-7-(5-chloropent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(150 mg, 0.365 mmol) and 4,4-difluoropiperidine hydrochloride (86 mg,0.548 mmol) in anhydrous acetonitrile (3 mL) at ambient temperature wasadded triethylamine (0.153 mL, 1.095 mmol) in one charge. The reactionwas sealed and heated in a Biotage Initiator microwave (absorptionsetting normal) to 150° C. for 30 minutes. The reaction was re-sealedand heated in a Biotage Initiator microwave (absorption setting normal)to 170° C. for 60 minutes. To the reaction was added further4,4-difluoropiperidine hydrochloride (86 mg, 0.548 mmol) andtriethylamine (0.153 mL, 1.095 mmol) and the reaction was re-sealed andheated in a Biotage Initiator microwave (absorption setting normal) to150° C. for 60 minutes. The reaction was concentrated in vacuo andpartitioned between DCM (10 mL) and water (10 mL). The organic wasseparated and dried (hydrophobic frit) and concentrated in vacuo beforebeing dissolved in DCM and purified by chromatography on aminopropylfunctionalised silica (11 g) using a 0-100% ethyl acetate:DCM gradientover 20 minutes. The material eluted at the solvent front and so did notcollect. The waste stream was concentrated in vacuo to give the titlecompound (77 mg).

LCMS (System A): t_(RET)=0.62 min; MH⁺ 496

Intermediate 68:5-((Benzyloxy)methyl)-2-butyl-7-(5-(4-fluoropiperidin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 54 from5-((benzyloxy)methyl)-2-butyl-7-(5-chloropent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amineand 4-fluoropiperidine hydrochloride.

LCMS (System B): t_(RET)=1.24 min; MH⁺ 478

Intermediate 69:5-((Benzyloxy)methyl)-7-(5-chloropent-1-yn-1-yl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 37 from5-((benzyloxy)methyl)-7-iodo-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amineand 5-chloropent-1-yne.

LCMS (System B): t_(RET)=1.11 min; MH⁺ 413, 415

Intermediate 70:5-((Benzyloxy)methyl)-7-(5-(4-fluoropiperidin-1-yl)ent-1-yn-1-yl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 54 from5-((benzyloxy)methyl)-7-(5-chloropent-1-yn-1-yl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amineand 4-fluoropiperidine hydrochloride.

LCMS (System B): t_(RET)=1.07 min; MH⁺ 480

Intermediate 71:1-(5-(4-Amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pent-4-yn-1-yl)piperidin-4-ol

Prepared similarly to Intermediate 54 from5-((benzyloxy)methyl)-2-butyl-7-(5-chloropent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amineand piperidin-4-ol.

LCMS (System B): t_(RET)=1.04 min; MH⁺ 476

Intermediate 72:(R)-5-((Benzyloxy)methyl)-2-butyl-7-(5-(3-fluoropyrrolidin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 54 from5-((benzyloxy)methyl)-2-butyl-7-(5-chloropent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amineand (R)-(−)-3-fluoropyrrolidine hydrochloride.

LCMS (System B): t_(RET)=1.18 min; MH⁺ 464

Intermediate 73:(S)-5-((Benzyloxy)methyl)-2-butyl-7-(5-(3-fluoropyrrolidin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 54 from5-((benzyloxy)methyl)-2-butyl-7-(5-chloropent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amineand (S)-(−)-3-fluoropyrrolidine hydrochloride.

LCMS (System B): t_(RET)=1.18 min; MH⁺ 464

Intermediate 74:(R)-5-((Benzyloxy)methyl)-7-(5-(3-fluoropyrrolidin-1-yl)pent-1-yn-1-yl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 54 from5-((benzyloxy)methyl)-7-(5-chloropent-1-yn-1-yl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amineand (R)-(−)-3-fluoropyrrolidine hydrochloride.

LCMS (System B): t_(RET)=1.02 min; MH⁺ 466

Intermediate 75:(S)-5-((Benzyloxy)methyl)-7-(5-(3-fluoropyrrolidin-1-yl)pent-1-yn-1-yl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 54 from5-((benzyloxy)methyl)-7-(5-chloropent-1-yn-1-yl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amineand (S)-(−)-3-fluoropyrrolidine hydrochloride.

LCMS (System B): t_(RET)=1.02 min; MH⁺ 466

Intermediate 76:(S)-1-(5-(4-Amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pent-4-yn-1-yl)pyrrolidin-3-ol

Prepared similarly to Intermediate 41 from5-(4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pent-4-ynaland (S)-3-pyrrolidinol.

LCMS (System B): t_(RET)=1.04 min; MH⁺ 462

Intermediate 77:1-(5-(4-Amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pent-4-yn-1-yl)azetidin-3-ol

A mixture of5-(4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pent-4-ynal(150 mg, 0.384 mmol), 3-hydroxyazetidine hydrochloride (84 mg, 0.768mmol) and triethylamine (0.107 mL, 0.768 mmol) in anhydrousdichloromethane (DCM) (2.5 mL) was stirred at room temperature undernitrogen for 1 hour. Molecular sieves were added to the reactionmixture. Sodium triacetoxyborohydride (163 mg, 0.768 mmol) was added andthe reaction was left to stir at room temperature for 1 hour. Thereaction mixture was filtered and water was added. The phases wereseparated, the aqueous phase were neutralised with aqueous 2M NaOHsolution and extracted with EtOAc. The organic layers were combined andconcentrated in vacuo.

the residue was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP(Method A). Fractions which contain the product were concentrated togive the title compound as an orange oil (68 mg).

LCMS (System B): t_(RET)=0.99 min; MH⁺ 448

Intermediate 78:5-((Benzyloxy)methyl)-2-butyl-7-(6-chlorohex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 37 from5-((benzyloxy)methyl)-2-butyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amineand 6-chlorohex-1-yne. The product was purified by in two stages,firstly by chromatography on silica using a 0-50% ethylacetate-dichloromethane gradient over 60 mins followed by purificationon an aminopropyl (NH2) cartridge (110 g) using a 0-100% ethylacetate-cyclohexane gradient over 40 mins.

LCMS (System B): t_(RET)=1.29 min; MH⁺ 425, 427

Intermediate 79:5-((Benzyloxy)methyl)-7-(6-chlorohex-1-yn-1-yl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 37 from5-((benzyloxy)methyl)-7-iodo-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amineand 6-chlorohex-1-yne.

LCMS (System B): t_(RET)=1.14 min; MH⁺ 427, 429

Intermediate 80:7-(6-(Azepan-1-yl)hex-1-yn-1-yl)-5-((benzyloxy)methyl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 54 from5-((benzyloxy)methyl)-7-(6-chlorohex-1-yn-1-yl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amineand azepane but with heating at 80° C. for 72 hours and purification onsilica using a 0-25% methanol-DCM gradient over 40 mins.

LCMS (System B): t_(RET)=1.10 min; MH⁺ 490

Intermediate 81:5-((Benzyloxy)methyl)-2-butyl-7-(6-(4-fluoropiperidin-1-yl)hex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a suspension5-((benzyloxy)methyl)-2-butyl-7-(6-chlorohex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(435 mg, 1.024 mmol) and 4-fluoropiperidine hydrochloride (367 mg, 2.63mmol) in acetonitrile (7 mL) was added triethylamine (0.856 mL, 6.14mmol) at ambient temperature. The reaction mixture was stirred at 60° C.under nitrogen for 88 h. The reaction mixture was evaporated in vacuo togive an brown solid which was partitioned between ethyl acetate (50 mL)and water (50 mL). The organic layer was separated, washed with brine(50 mL), dried using a hydrophobic frit and concentrated in vacuo togive a brown oil. This crude product was purified by sequentialchromatography on aminopropyl (NH2) cartridge using firstly a 0-50%ethyl acetate-cyclohexane gradient and then a 0-100% tert-butyl methylether (TBME)-cyclohexane gradient and finally a 0-10%methanol-dichloromethane gradient. Final purification by MDAP (Method B)gave the title compound as an off-white solid (50 mg).

LCMS (System B): t_(RET)=1.24 min; MH⁺ 492

Intermediate 82:(R)-5-((Benzyloxy)methyl)-2-butyl-7-(6-(3-fluoropyrrolidin-1-yl)hex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 54 from5-((benzyloxy)methyl)-2-butyl-7-(6-chlorohex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amineand (R)(−)3-fluoropyrrolidine hydrochloride but with heating at 60° C.for 88 hours and purification on aminopropyl (NH2) cartridge using a0-50% ethyl acetate-cyclohexane gradient.

LCMS (System B): t_(RET)=1.20 min; MH⁺ 478

Intermediate 83:(S)-5-((Benzyloxy)methyl)-2-butyl-7-(6-(3-fluoropyrrolidin-1-yl)hex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 82 from5-((benzyloxy)methyl)-2-butyl-7-(6-chlorohex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amineand (S)(+)3-fluoropyrrolidine hydrochloride

LCMS (System B): t_(RET)=1.20 min; MH⁺ 478

Intermediate 84:(S)-5-((Benzyloxy)methyl)-2-butyl-7-(5-(2-methylpyrrolidin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a stirred solution of5-((benzyloxy)methyl)-2-butyl-7-(5-chloropent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(200 mg, 0.487 mmol) in acetonitrile (4 mL) was added triethylamine(0.204 mL, 1.460 mmol) and (S)-2-methylpyrrolidine (0.149 mL, 1.460mmol). The resultant mixture was heated at 60° C. for 72 h when more(S)-2-methylpyrrolidine (0.05 mL, 0.49 mmol) and triethylamine (0.068mL, 0.49 mmol) were added and the reaction heated to 80° C. for 5 h. Thereaction mixture was concentrated in vacuo and the residue partitionedbetween DCM (20 mL) and water (20 mL). The organic layer was separatedand dried (hydrophobic frit) before concentration in vacuo to give a redoil. This material was dissolved in dichloromethane and purified on anaminopropyl functionalised silica cartridge (11 g) using a 0-50% ethylacetate-cyclohexane gradient over 40 mins. The appropriate fractionswere combined and evaporated in vacuo to give the title compound as as acolourless oil which solidified (142 mg).

LCMS (System B): t_(RET)=1.15 min; MH⁺ 460

Intermediate 85:(R)-5-((Benzyloxy)methyl)-2-butyl-7-(5-(2-methylpyrrolidin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 84 from5-((benzyloxy)methyl)-2-butyl-7-(5-chloropent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amineand (R)-2-methylpyrrolidine.

LCMS (System B): t_(RET)=1.12 min; MH⁺ 460

Intermediate 86:5-((Benzyloxy)methyl)-2-butyl-7-(5-(3-methylazetidin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a stirred suspension of5-(4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pent-4-ynal(90 mg, 0.230 mmol) and 4 A molecular sieves in anhydrous DCM (4 mL)under nitrogen was added a solution of 3-methylazetidine hydrochloride(28 mg, 0.260 mmol) and triethylamine (0.04 mL, 0.287 mmol) in anhydrousDCM (1 mL). The reaction mixture was stirred at ambient temperature for1 min before addition of sodium triacetoxyborohydride (98 mg, 0.461mmol) and stirring was continued at ambient temperature for 4 h. Thereaction mixture was diluted with DCM (15 mL) and filtered throughcelite. The filtrate was washed with saturated aqueous sodiumbicarbonate (20 mL), dried (hydrophobic frit) and concentrated in vacuoto give a brown oil. This material was dissolved in dichloromethane andpurified on an aminopropyl functionalised silica cartridge (11 g) usinga 0-100% ethyl acetate-cyclohexane gradient over 30 mins. Theappropriate fractions were combined and evaporated in vacuo to give thetitle compound as a colourless oil (33 mg).

LCMS (System B): t_(RET)=1.19 min; MH⁺ 446

Intermediate 87:5-((Benzyloxy)methyl)-2-butyl-7-(5-(3-fluoroazetidin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 86 from5-(4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pent-4-ynaland 3-fluoroazetidine hydrochloride

LCMS (System B): t_(RET)=1.12 min; MH⁺ 450

Intermediate 88:5-((Benzyloxy)methyl)-2-butyl-6-methyl-7-(6-(pyrrolidin-1-yl)hex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a stirred solution of5-((benzyloxy)methyl)-2-butyl-7-(6-chlorohex-1-yn-1-yl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine(160 mg, 0.364 mmol) and triethylamine (0.152 mL, 1.093 mmol) inacetonitrile (4 mL) was added pyrrolidine (0.090 mL, 1.093 mmol). Thereaction was stirred at 80° C. for 18 h when more pyrrolidine (0.045 mL,0.547 mmol) and triethylamine (0.075 mL, 0.539 mmol) were added and themixture was stirred at 80° C. for a further 2 h. The reaction mixturewas then concentrated in vacuo at 60° C. and the residue paritionedbetween DCM (25 mL) and water (25 mL). The organic layer was separatedand the aqueous layer back-extracted with DCM (2×25 mL). The combinedorganic phases were dried through a hydrophobic frit and concentrated invacuo to give an orange-brown solid. This material was loaded indichloromethane and purified on aminopropyl (NH2) cartridge (10 g) usinga 0-50% ethyl acetate-DCM gradient over 40 mins. The appropriatefractions were combined and evaporated in vacuo to give the titlecompound as a pale yellow gum (157 mg).

LCMS (System B): t_(RET)=1.18 min; MH⁺ 474

Intermediate 89:5-((Benzyloxy)methyl)-2-butyl-7-(5-(4-fluoropiperidin-1-yl)pent-1-yn-1-yl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a stirred solution of5-((benzyloxy)methyl)-2-butyl-7-(5-chloropent-1-yn-1-yl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine(140 mg, 0.329 mmol) in acetonitrile (3 mL) was added triethylamine(0.276 mL, 1.977 mmol) and 4-fluoropiperidine hydrochloride (138 mg,0.988 mmol). The resultant mixture was heated at 60° C. for 18 h whenmore 4-fluoropiperidine hydrochloride (50 mg, 0.36 mmol) andtriethylamine (0.1 mL, 0.72 mmol) were added and heating at 60° C.continued for 20 h. More triethylamine (0.1 mL, 0.72 mmol) was added andthe mixture heated to 80° C. for a further 4 h. The reaction mixture wasconcentrated in vacuo and the residue partitioned between DCM (20 mL)and water (20 mL). The organic layer was separated and dried(hydrophobic frit) before concentration in vacuo to a red oil. Thismaterial was dissolved in dichloromethane and purified on an aminopropylfunctionalised silica cartridge (11 g) using a 0-100% ethylacetate-cyclohexane gradient over 30 mins. The appropriate fractionswere combined and evaporated in vacuo to give the title compound as acolourless gum (85 mg).

LCMS (System B): t_(RET)=1.24 min; MH⁺ 492

Intermediate 90:(S)-5-((Benzyloxy)methyl)-2-butyl-7-(5-(3-fluoropyrrolidin-1-yl)pent-1-yn-1-yl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a stirred solution of5-((benzyloxy)methyl)-2-butyl-7-(5-chloropent-1-yn-1-yl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine(334 mg, 0.786 mmol) in DMF (6 mL) was added triethylamine (0.657 mL,4.72 mmol) and (S)-3-fluoropyrrolidine hydrochloride (296 mg, 2.358mmol). The resultant mixture was heated at 60° C. for 52 h and thenconcentrated in vacuo. The residue was partitioned between DCM (40 mL)and water (40 mL) and the organic layer was separated. The aqueous layerwas re-extracted with DCM (50 mL) and the organic extracts werecombined, dried (hydrophobic frit) and concentrated in vacuo to give ayellow oil (534 mg). This crude product was dissolved in dichloromethaneand loaded onto an aminopropyl (NH2) cartridge (50 g) and eluted with a0-100% ethyl acetate-cyclohexane gradient over 60 min. The appropriatefractions were combined and evaporated in vacuo to give the titlecompound as a colourless oil (265.7 mg).

LCMS (System B): t_(RET)=1.19 min; MH⁺ 478

Intermediate 91:(R)-5-((Benzyloxy)methyl)-2-butyl-7-(5-(3-fluoropyrrolidin-1-yl)pent-1-yn-1-yl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 89 from5-((benzyloxy)methyl)-2-butyl-7-(5-chloropent-1-yn-1-yl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amineand (R)-3-fluoropyrrolidine hydrochloride.

LCMS (System B): t_(RET)=1.20 min; MH⁺ 478

Intermediate 92:5-((Benzyloxy)methyl)-2-butyl-7-(5-(3-fluoroazetidin-1-yl)pent-1-yn-1-yl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 86 from5-(4-amino-5-((benzyloxy)methyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pent-4-ynaland 3-fluoroazetidine hydrochloride

LCMS (System B): t_(RET)=1.16 min; MH⁺ 464

Intermediate 93:5-((Benzyloxy)methyl)-2-(2-methoxyethyl)-7-(5-(pyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Intermediate 89 from5-((benzyloxy)methyl)-7-(5-chloropent-1-yn-1-yl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amineand pyrrolidine.

LCMS (System B): t_(RET)=1.01 min; MH⁺ 448

EXAMPLE PREPARATION Example 1:2-Butyl-7-(6-(piperidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amineformate

Method A

A solution of5-((benzyloxy)methyl)-2-butyl-7-(6-(piperidin-1-yl)hex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(157 mg, 0.331 mmol) in ethanol (15 ml) was passed through the H-cube(settings: 20° C., full hydrogen, 1 mL/min flow rate and 10% palladiumon carbon CatCart30 as the catalyst). A new 10% palladium on carbonCatCart30 cartridge was inserted into the H-cube and the solution waspassed again through the H-cube (settings: 40° C., full hydrogen, 1mL/min flow rate). The process was repeated a further twice using a newcartridge and identical settings on each occasion. The solution wasevaporated in-vacuo to yield a white solid. The solid was dissolved inDMSO (7×1 ml) and purified by MDAP (Method A). Appropriate fractionswere combined and evaporated in vacuo to yield the title compound as acolourless oil (66 mg).

LCMS (System A): t_(RET)=0.50 min; MH⁺ 358

Method B

A mixture of2-butyl-7-(6-(piperidin-1-yl)hexyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(50 mg, 0.103 mmol), ethylenediamine (11 μl, 0.163 mmol) andtetrabutylammonium fluoride 1 M in tetrahydrofuran (310 μl, 0.310 mmol)was heated to 70° C. for 3.5 hours. The reaction was concentrated invacuo and the residue was dissolved in 1:1 MeOH:DMSO (1 mL) and purifiedby MDAP (Method A). The solvent was dried under a stream of nitrogen inthe Radleys blowdown apparatus to give the title compound (23 mg).

LCMS (System B): t_(RET)=1.03 min; MH⁺ 358

Example 2:2-Butyl-7-(5-(piperidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

5-((Benzyloxy)methyl)-2-butyl-7-(5-(piperidin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (70 mg, 0.152 mmol)in ethanol (20 ml) was filtered and passed through the H-cube (settings:20° C., full hydrogen, 1 mL/min flow rate and 10% palladium on carbonCatCart30 as the catalyst). A new 10% palladium on carbon CatCart30cartridge was inserted into the H-cube and the solution was passed againthrough the H-cube (settings: 45° C., full hydrogen, 1 mL/min flowrate). The process was repeated using a new CatCart each time then thesolution was evaporated in vacuo to yield a white solid. The solid wasdissolved in MeOH:DMSO (1:1) (1 ml) and purified by MDAP (Method A).Appropriate fractions were combined and evaporated in vacuo to yield thetitle compound as a colourless oil (4.8 mg).

LCMS (System B): t_(RET)=0.94 min; MH⁺ 344

Example 3:2-Butyl-7-(4-(piperidin-1-yl)butyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

A solution of5-((benzyloxy)methyl)-2-butyl-7-(4-(piperidin-1-yl)but-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(95 mg, 0.213 mmol) in ethanol (20 mL) was passed through the H-cube(settings: 20° C., full hydrogen, 1 mL/min flow rate and 10% palladiumon carbon CatCart30 as the catalyst). A new 10% palladium on carbonCatCart30 cartridge was inserted into the H-cube and the solution waspassed again through the H-cube (settings: 45° C., full hydrogen, 1mL/min flow rate). The process was repeated a further twice using a newCatCart each time. The solution was evaporated in vacuo to yield a whitesolid. The solid was dissolved in MeOH:DMSO (1:1) (1 mL) and purified byMDAP (Method B). The appropriate fraction was evaporated in vacuo toyield the title compound as a white solid (6.43 mg).

LCMS (System B): t_(RET)=0.90 min; MH⁺ 330

Example 4:2-(Ethoxymethyl)-7-(6-(piperidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

A solution of5-((benzyloxy)methyl)-2-(ethoxymethyl)-7-(6-(piperidin-1-yl)hex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(0.296 mL, 0.296 mmol) in methanol (15 mL) was passed through the H-cube(settings: 45° C., full hydrogen, 1 mL/min flow rate and 10% palladiumon carbon CatCart30 as the catalyst). The solution was re-run throughthe H-cube (same settings) then concentrated in vacuo. The residue wasdissolved in 50:50 DMSO/MeOH (2 mL) and purified by MDAP (Method B). Thefractions which contained product were concentrated to give the titlecompound as a white solid (41 mg).

LCMS (System B): t_(RET)=0.87 min; MH⁺ 360

Example 5:2-(2-Methoxyethyl)-7-(6-(piperidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-aminehydrochloride

A solution of5-((benzyloxy)methyl)-2-(2-methoxyethyl)-7-(6-(piperidin-1-yl)hex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(95.5 mg, 0.201 mmol) in methanol (15 mL) was hydrogenated using theH-Cube (settings: 60° C., full H₂, 1 mL/min flow rate) and 10% Pd/CCatCart 30 as the catalyst. The methanol was removed in vacuo to give awhite solid. The sample was dissolved in 1:1 MeOH:DMSO (1 mL) andpurified by MDAP (Method A). The solvent was dried under a stream ofnitrogen in the Radleys blowdown apparatus to give the formate salt (31mg). 4M HCl in dioxane was added and the product was dried under astream of nitrogen in the Radleys blowdown apparatus to give the titlecompound (34 mg).

LCMS (System B): t_(RET)=0.84 min; MH⁺ 360

Example 6:2-Butyl-6-methyl-7-(6-(piperidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

A solution of5-((benzyloxy)methyl)-2-butyl-6-methyl-7-(6-(piperidin-1-yl)hex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(0.275 mL, 0.275 mmol) in methanol (15 mL) was passed through the H-cube(settings: 40° C., full hydrogen, 1 mL/min flow rate and 10% palladiumon carbon CatCart30 as the catalyst). The solution was re run throughthe H-cube (same settings) then evaporated in vacuo to yield a palebrown oil (35 mg). The compound was dissolved in 1 mL of 50:50 DMSO/MeOHand the crude product was purified by MDAP (Method B). Fractions whichcontained product were concentrated to give the title compound as awhite solid (22 mg).

LCMS (System B): t_(RET)=1.08 min; MH⁺ 372

Example 7:2-Butyl-6-methyl-7-(5-(piperidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 3 from5-((benzyloxy)methyl)-2-butyl-6-methyl-7-(5-(piperidin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=1.02 min; MH⁺ 358

Example 8:2-Butyl-6-methyl-7-(4-(piperidin-1-yl)butyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 4 from5-((benzyloxy)methyl)-2-butyl-6-methyl-7-(4-(piperidin-1-yl)but-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=0.98 min; MH⁺ 344

Example 9:2-Butyl-7-(5-(pyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amineformate

A solution of5-((benzyloxy)methyl)-2-butyl-7-(5-(pyrrolidin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(90 mg, 0.202 mmol) in ethanol (10 mL) was hydrogenated using the H-cube(settings: 60° C., Full H₂, 1 mL/min flow rate) and 10% Pd/C CatCart 30as the catalyst. The reaction mixture was passed through the H-cubeagain using identical conditions. The reaction was concentrated invacuo. The residue were dissolved in 1:1 MeOH:DMSO 1 mL and purified byMDAP (Method A). The solvent was dried under a stream of nitrogen in theRadleys blowdown apparatus to give the title compound as a white gum (16mg).

LCMS (System A): t_(RET)=0.44 min; MH⁺ 330

Example 10:2-Butyl-7-(6-(pyrrolidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

A solution of5-((benzyloxy)methyl)-2-butyl-7-(6-(pyrrolidin-1-yl)hex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(55 mg, 0.120 mmol) in ethanol (4.5 mL) and acetic acid (0.5 mL) washydrogenated using the H-cube (settings: 60° C., Full H₂, 1 mL/min flowrate) and 10% Pd/C CatCart 30 as the catalyst. The reaction mixture wasconcentrated in vacuo at 60° C. to give a colourless oil (45 mg). Thesamples was dissolved in 1:1 DMF:DMSO (1 mL) and purified by MDAP(Method B). The majority of the solvent was evaporated in vacuo at 60°C. and the remainder removed in a Radleys blowdown apparatus at 50° C.to give the title compound as a white solid (20 mg).

LCMS (System B): t_(RET)=0.93 min; MH⁺ 342

Example 11:2-Pentyl-7-(6-(piperidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 10 from5-((benzyloxy)methyl)-2-pentyl-7-(6-(piperidin-1-yl)hex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=1.17 min; MH⁺ 372

Example 12:7-(5-(Azepan-1-yl)pentyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 10 from7-(5-(azepan-1-yl)pent-1-yn-1-yl)-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=0.89 min; MH⁺ 358

Example 13:7-(4-(Azepan-1-yl)butyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 10 from7-(4-(azepan-1-yl)butyl)-5-((benzyloxy)methyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=0.93 min; MH⁺ 358

Example 14:2-Butyl-6-methyl-7-(6-(pyrrolidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 10 from5-((benzyloxy)methyl)-2-butyl-6-methyl-7-(6-(pyrrolidin-1-yl)hex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=0.94 min; MH⁺ 358

Example 15:7-(6-(Azetidin-1-yl)hexyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 10 from7-(6-(azetidin-1-yl)hex-1-yn-1-yl)-5-((benzyloxy)methyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=0.96 min; MH⁺ 342

Example 16:2-Butyl-6-methyl-7-(5-(pyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 10 from5-((benzyloxy)methyl)-2-butyl-6-methyl-7-(5-(pyrrolidin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=0.89 min; MH⁺ 344

Example 17:7-(5-(Azetidin-1-yl)pentyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 10 from7-(5-(azetidin-1-yl)pent-1-yn-1-yl)-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=0.89 min; MH⁺ 316

Example 18:7-(5-(Azetidin-1-yl)pentyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 10 from7-(5-(azetidin-1-yl)pent-1-yn-1-yl)-5-((benzyloxy)methyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=0.82 min; MH⁺ 330

Example 19:2-Butyl-6-methyl-7-(4-(pyrrolidin-1-yl)butyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 10 from5-((benzyloxy)methyl)-2-butyl-6-methyl-7-(4-(pyrrolidin-1-yl)butyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

LCMS (System B): t_(RET)=1.00 min; MH⁺ 330

Example 20:2-Butyl-7-(5-(4,4-difluoropiperidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 10 from5-((benzyloxy)methyl)-2-butyl-7-(5-(4,4-difluoropiperidin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

LCMS (System B): t_(RET)=1.06 min; MH⁺ 380

Example 21:2-Butyl-7-(5-(4-fluoropiperidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 10 from5-((benzyloxy)methyl)-2-butyl-7-(5-(4-fluoropiperidin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=1.00 min; MH⁺ 362

Example 22:7-(5-(4-Fluoropiperidin-1-yl)pentyl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 10 from5-((benzyloxy)methyl)-7-(5-(4-fluoropiperidin-1-yl)pent-1-yn-1-yl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=0.81 min; MH⁺ 364

Example 23:1-(5-(4-Amino-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pentyl)piperidin-4-ol

Prepared similarly to Example 10 from1-(5-(4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pent-4-yn-1-yl)piperidin-4-ol.

LCMS (System B): t_(RET)=0.75 min; MH⁺ 360

Example 24:(R)-2-Butyl-7-(5-(3-fluoropyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 10 from(R)-5-((benzyloxy)methyl)-2-butyl-7-(5-(3-fluoropyrrolidin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=0.93 min; MH⁺ 348

Example 25:(S)-2-Butyl-7-(5-(3-fluoropyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 10 from(S)-5-((benzyloxy)methyl)-2-butyl-7-(5-(3-fluoropyrrolidin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=0.93 min; MH⁺ 348

Example 26:(R)-7-(5-(3-Fluoropyrrolidin-1-yl)pentyl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amineformate

A solution of crude(R)-5-((benzyloxy)methyl)-7-(5-(3-fluoropyrrolidin-1-yl)pent-1-yn-1-yl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(278 mg, 0.597 mmol) in ethanol (25 mL) and acetic Acid (2.5 mL) washydrogenated using the H-cube (settings: 60° C., Full H₂, 1 mL/min flowrate) and 10% Pd/C CatCart 30 as the catalyst. The material was re run 3times through the H-cube. The crude material was dissolved in DMSO/MeOH(3 mL) and a sample (1 mL) purified by MDAP (Method A). Fractionscontaining desired product were combined and concentrated in vacuo togive the title compound as a clear oil (31.3 mg).

LCMS (System B): t_(RET)=0.75 min; MH⁺ 350

Example 27:(S)-7-(5-(3-Fluoropyrrolidin-1-yl)pentyl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amineformate

Prepared similarly to Example 26 from(S)-5-((benzyloxy)methyl)-7-(5-(3-fluoropyrrolidin-1-yl)pent-1-yn-1-yl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=0.73 min; MH⁺ 350

Example 28:(S)-1-(5-(4-Amino-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pentyl)pyrrolidin-3-ol

Prepared similarly to Example 10 from(S)-1-(5-(4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pent-4-yn-1-yl)pyrrolidin-3-ol.

LCMS (System B): t_(RET)=0.77 min; MH⁺ 348

Example 29:1-(5-(4-Amino-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pentyl)azetidin-3-olformate

Prepared similarly to Example 27 from1-(5-(4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pent-4-yn-1-yl)azetidin-3-ol.

LCMS (System B): t_(RET)=0.73 min; MH⁺ 332

Example 30:7-(6-(Azepan-1-yl)hexyl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 10 from7-(6-(azepan-1-yl)hex-1-yn-1-yl)-5-((benzyloxy)methyl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=0.82 min; MH⁺ 374

Example 31:2-Butyl-7-(6-(4-fluoropiperidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 10 from5-((benzyloxy)methyl)-2-butyl-7-(6-(4-fluoropiperidin-1-yl)hex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=1.00 min; MH⁺ 376

Example 32:(R)-2-Butyl-7-(6-(3-fluoropyrrolidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 10 from(R)-5-((benzyloxy)methyl)-2-butyl-7-(6-(3-fluoropyrrolidin-1-yl)hex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-aminebut using 5% Pd/C CatCart 30 cartridges and running twice through theH-cube.

LCMS (System B): t_(RET)=0.96 min; MH⁺ 362

Example 33:(S)-2-Butyl-7-(6-(3-fluoropyrrolidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 32 from(S)-5-((benzyloxy)methyl)-2-butyl-7-(6-(3-fluoropyrrolidin-1-yl)hex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=0.95 min; MH⁺ 362

Example 34:(S)-2-Butyl-7-(5-(2-methylpyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 10 from(S)-5-((benzyloxy)methyl)-2-butyl-7-(5-(2-methylpyrrolidin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=0.86 min; MH⁺ 344

Example 35:(R)-2-Butyl-7-(5-(2-methylpyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 34 from(R)-5-((benzyloxy)methyl)-2-butyl-7-(5-(2-methylpyrrolidin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-aminebut with passing twice through the H-cube using the same 10% Pd/CCatCart 30 cartridge.

LCMS (System B): t_(RET)=0.85 min; MH⁺ 344

Example 36:2-Butyl-7-(5-(3-methylazetidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 10 from5-((benzyloxy)methyl)-2-butyl-7-(5-(3-methylazetidin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=0.90 min; MH⁺ 330

Example 37:2-Butyl-7-(5-(3-fluoroazetidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 35 from5-((benzyloxy)methyl)-2-butyl-7-(5-(3-fluoroazetidin-1-yl)pent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=0.89 min; MH⁺ 334

Example 38:2-Butyl-6-methyl-7-(6-(pyrrolidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 35 from5-((benzyloxy)methyl)-2-butyl-6-methyl-7-(6-(pyrrolidin-1-yl)hex-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=0.94 min; MH⁺ 358

Example 39:2-Butyl-7-(5-(4-fluoropiperidin-1-yl)pentyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 10 from5-((benzyloxy)methyl)-2-butyl-7-(5-(4-fluoropiperidin-1-yl)pent-1-yn-1-yl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-aminebut in this case the product obtained from the MDAP was dissolved in DCM(10 mL) and washed with saturated aqueous sodium bicarbonate (10 mL).The organic phase was separated and the aqueous layer back extractedwith 1:1 ethyl acetate:chloroform (3×10 mL). The combined organicextracts were dried (hydrophobic frit) and concentrated in vacuo to givethe title compound as a white solid (19 mg).

LCMS (System B): t_(RET)=1.01 min; MH⁺ 376

Example 40:(S)-2-Butyl-7-(5-(3-fluoropyrrolidin-1-yl)pentyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

(S)-5-((benzyloxy)methyl)-2-butyl-7-(5-(3-fluoropyrrolidin-1-yl)pent-1-yn-1-yl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine(265.7 mg, 0.556 mmol) was dissolved in methanol (30 mL) and acetic acid(3 mL) and hydrogenated using the H-cube (settings: 60° C., fullhydrogen, 1 mL/min flow rate) and 10% Pd/C CatCart 30 as the catalyst.The mixture was passed though the H-cube a second time and then themethanol was evaporated and the crude material was purified MDAP (MethodB). Appropriate fractions were combined and evaporated in vacuo to yieldthe title compound as a clear oil (116 mg).

LCMS (System B): t_(RET)=0.92 min; MH⁺ 362

Example 41:(R)-2-Butyl-7-(5-(3-fluoropyrrolidin-1-yl)pentyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 10 from(R)-5-((benzyloxy)methyl)-2-butyl-7-(5-(3-fluoropyrrolidin-1-yl)pent-1-yn-1-yl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=0.96 min; MH⁺ 362

Example 42:2-Butyl-7-(5-(3-fluoroazetidin-1-yl)pentyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 10 from5-((benzyloxy)methyl)-2-butyl-7-(5-(3-fluoroazetidin-1-yl)pent-1-yn-1-yl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=0.91 min; MH⁺ 348

Example 43:2-(2-Methoxyethyl)-7-(5-(pyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

Prepared similarly to Example 10 from5-((benzyloxy)methyl)-2-(2-methoxyethyl)-7-(5-(pyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.

LCMS (System B): t_(RET)=0.70 min; MH⁺ 332

Biological Evaluation

Compounds of the invention were tested for in vitro biological activityin accordance with the following assay.

Assay for the Induction of Interferon-□ □and TNF-□ Using Fresh HumanWhole Blood (WB) Compound Preparation

Compounds were prepared at 100× required concentration in DMSO inflat-bottom microtitre plates at a volume of 1.5 μL. Columns 1-10contained a 1 in 4 serial dilution of the test compound. Included oneach plate was a serial dilution of the TLR7/8 agonist resiquimod as astandard and Column 11 contained 1.5 μl of 200 μM resiquimod (giving a 2μM final concentration, used to define the approximate maximal responseto resiquimod). Each compound was assayed in duplicate for each donor.

Incubation and Assays for Interferon-α and TNF-α

Blood samples from three human donors were collected into sodium heparin(10 U/ml). 150 μl of whole Blood was dispensed into Col 1 to 11 of assayplates containing 1.5 μl of test compound or standard in DMSO. Plateswere placed in an incubator overnight (37° C., 95% air, 5% CO₂).Following the overnight incubation, plates were removed from theincubator & mixed on an orbital shaker for approximately 1 minute. 100μl of 0.9% saline was added to each well and the plates mixed again onan orbital shaker. Plates were then centrifuged (2500 rpm, 10 mins),after which a sample of plasma was removed using a Biomek FX and assayedfor both IFN-α and TNF-α using the MSD (Mesoscale Discovery)electrochemiluminescence assay platform. The IFN-α assay was carried outsimilarly to that described above. The TNF-α assay was carried out asper kit instructions (Cat No K111BHB).

Cytokine released was expressed as a percentage of the 2 μM resiquimodcontrol (column 11). This percentage was plotted against compoundconcentration and the pEC₅₀ for the response determined by non-linearleast squares curve fitting. For the IFN-α responses, generally a 4parameter logistic model was selected. For the TNF-α responses where aclear maximum response was obtained (i.e. a well defined plateau in theresponse was observed) then a 4 parameter model was generally used. Ifthe upper asymptote of the curve wasn't well defined then the curvefitting was generally constrained to a maximal response of 100% (i.e. tothe response to 2 μM resiquimod) or to the response of the highestconcentration tested if this was greater than the resiquimod response.Some curves were bell shaped for one or both cytokines and the cytokinedata on the down slope of the bell shaped response (i.e. concentrationsabove those giving the maximal response) were generally excluded fromthe fit, usually with the exception of the concentration immediatelyabove the peak response. Curve fitting thus concentrated on the up slopeof the dose response curve.

Results

Examples 1 to 43 had a mean pEC₅₀ for IFN-α≥25.3.

Examples 1 to 43 had a mean pEC₅₀ for TNF-α of ≤5.3.

1. A method of treating allergic disease, inflammatory disease, orautoimmune disease in a human in need thereof, the method comprisingadministering to the human a compound of formula (I) or apharmaceutically acceptable salt thereof:

wherein: R₁ is n-C₄₋₆alkyl or C₁₋₂alkoxyC₁₋₂alkyl-; R₂ is hydrogen ormethyl; each R₃ is hydroxy, halo or n-C₁₋₃alkyl; m is an integer havinga value of 2 to 4; n is an integer having a value of 0 to 3; p is aninteger having a value of 0 to 2; and administering to the human atleast one other therapeutically active agent.
 2. The method according toclaim 1 wherein R₁ is n-butyl.
 3. The method according to claim 1wherein R₁ is ethoxymethyl.
 4. The method according to claim 1 whereinR₁ is 2-methoxyethyl.
 5. The method according to claim 1 wherein R₂ ishydrogen.
 6. The method according to claim 1 wherein R₂ is methyl. 7.The method according to claim 1 wherein n is an integer having a valueof 1 or
 2. 8. The method according to claim 1 wherein p is
 0. 9. Themethod according to claim 1 wherein R₃ is hydroxy or halo.
 10. Themethod according to claim 1 wherein p is 1 and R₃ is hydroxy or fluoro.11. The method according to claim 1 wherein p is 2 and R₃ is fluoro. 12.The method according to claim 1 wherein the compound is selected fromthe group consisting of:2-Butyl-7-(6-(piperidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;2-Butyl-7-(5-(piperidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;2-Butyl-7-(4-(piperidin-1-yl)butyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;2-(Ethoxymethyl)-7-(6-(piperidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;2-(2-Methoxyethyl)-7-(6-(piperidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;2-Butyl-6-methyl-7-(6-(piperidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;2-Butyl-6-methyl-7-(5-(piperidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;2-Butyl-6-methyl-7-(4-(piperidin-1-yl)butyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;2-Butyl-7-(5-(pyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;2-Butyl-7-(6-(pyrrolidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;2-Pentyl-7-(6-(piperidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;7-(5-(Azepan-1-yl)pentyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine;7-(4-(Azepan-1l-yl)butyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine;2-Butyl-6-methyl-7-(6-(pyrrolidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;7-(6-(Azetidin-1-yl)hexyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine;2-Butyl-6-methyl-7-(5-(pyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;7-(5-(Azetidin-1-yl)pentyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine;7-(5-(Azetidin-1-yl)pentyl)-2-butyl-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine;2-Butyl-6-methyl-7-(4-(pyrrolidin-1-yl)butyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;2-Butyl-7-(5-(4,4-difluoropiperidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;2-Butyl-7-(5-(4-fluoropiperidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;7-(5-(4-Fluoropiperidin-1-yl)pentyl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;1-(5-(4-Amino-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pentyl)piperidin-4-ol;(R)-2-Butyl-7-(5-(3-fluoropyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;(S)-2-Butyl-7-(5-(3-fluoropyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;(R)-7-(5-(3-Fluoropyrrolidin-1-yl)pentyl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;(S)-7-(5-(3-Fluoropyrrolidin-1-yl)pentyl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;(S)-1-(5-(4-Amino-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pentyl)pyrrolidin-3-ol;1-(5-(4-Amino-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pentyl)azetidin-3-ol;7-(6-(Azepan-1-yl)hexyl)-2-(2-methoxyethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;2-Butyl-7-(6-(4-fluoropiperidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;(R)-2-Butyl-7-(6-(3-fluoropyrrolidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;(S)-2-Butyl-7-(6-(3-fluoropyrrolidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;(S)-2-Butyl-7-(5-(2-methylpyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;(R)-2-Butyl-7-(5-(2-methylpyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;2-Butyl-7-(5-(3-methylazetidin-1l-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;2-Butyl-7-(5-(3-fluoroazetidin-1l-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;2-Butyl-6-methyl-7-(6-(pyrrolidin-1-yl)hexyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;2-Butyl-7-(5-(4-fluoropiperidin-1-yl)pentyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine;(S)-2-Butyl-7-(5-(3-fluoropyrrolidin-1-yl)pentyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine;(R)-2-Butyl-7-(5-(3-fluoropyrrolidin-1-yl)pentyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine;2-Butyl-7-(5-(3-fluoroazetidin-1-yl)pentyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine;and2-(2-Methoxyethyl)-7-(5-(pyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.13. The method according to claim 1 wherein the compound is2-butyl-7-(5-(pyrrolidin-1-yl)pentyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine:


14. The method according to claim 1 wherein the compound is in the formof a pharmaceutically acceptable salt.
 15. The method according to claim1 wherein the compound is in the form of a free base.
 16. The methodaccording to claim 1 wherein the allergic disease, inflammatory disease,or autoimmune disease is asthma.
 17. The method according to claim 1wherein the allergic disease, inflammatory disease, or autoimmunedisease is allergic rhinitis.
 18. The method according to claim 1wherein the at least one other therapeutically active agent is selectedfrom an antigen immunotherapy, an anti-histamine, a steroid, an NSAID, abronchodilator, methotrexate, a leukotriene modulator, monoclonalantibody therapy, receptor therapy, and antigen non-specificimmunotherapy.